Substituted 3,4-dihydroxy phenylethylamino compounds

ABSTRACT

Novel compounds of the formula ##STR1## in which one of R 30  and R 40  represents a substituted phenylalkyl group, 
     the other of R 30  and R 40  represents hydrogen or halogen, and 
     R 50  and R 60  each independently represent hydrogen or alkyl; in addition R 60  may represent a substituted alkyl chain interrupted by N. 
     The compounds of the invention are useful for the treatment or prophylaxis of renal failure or cardiovascular disease.

This application is a continuation-in-part of U.S. application Ser. No.932,473 filed on Nov. 19, 1986.

This invention relates to novel compounds, compositions thereof andprocesses for their preparation.

We have now found a novel group of catecholamine derivatives which mayalso be used in the treatment or prophylaxis of renal failure orcardiovascular disorders.

According to the invention there are provided compounds of formula I,##STR2## in which one of R₃₀ and R₄₀ represents a group Ra, ##STR3## andthe other of R₃₀ and R₄₀ represents hydrogen or halogen, R₅₀ and R₆₀,which may be the same or different, each independently representhydrogen or alkyl C 1 to C6;

in addition R₆₀ may represent a group Rb,

    CH.sub.2 XCH.sub.2 YCHR.sub.15 ZR.sub.10                   Rb

wherein

X represents a C2 to C8 alkylene chain optionally interrupted by adouble bond or by S(O)_(n), wherein n is 0, 1 or 2, Z represents a C 1to C3 alkylene chain, each of X and Z being optionally substituted by OHor one or more alkyl C 1 to C6,

Y represents NR₇₀,

R₇₀ represents hydrogen, alkyl C 1 to C6 or (CH₂)_(q) R₁₁,

R₁₀ and R₁₁ independently represent phenyl substituted by one or moresubstituents R₂₃, which may be the same or different; or R₁₀ representsa saturated carbocyclic group,

R₁₅ represents hydrogen, alkyl C 1 to C6, or together with R₂₃ forms a(CH₂)p chain, wherein p represents 0, 1 or 2,

R₂₀, R₂₁, R₂₂ and R₂₃ independently represent hydrogen, alkyl C 1 to C6,NHR₂₅, SH, NO₂, halogen, CF₃, SO₂ R₂₆, CH₂ OH or OH, wherein R₂₅represents hydrogen, alkyl C 1 to C6 or alkanoyl C 1 to C6 and R₂₆represents alkyl C 1 to C6 or NH₂

m represents 2, 3 or 4,

q represents an integer from 1 to 6 inclusive, provided that

(a) when R₁₅, R₂₁, R₂₂, R₂₃, R₄₀, R₅₀ and R₇₀ represent hydrogen, mrepresents 2, X represents unsubstituted and uninterrupted (CH₂)₄, Zrepresents CH₂, R₁₀ represents phenyl, then R₂₀ does not representhydrogen or 4-OH, and

(b) when R₄₀ and R₅₀ both represent hydrogen, then in addition Y mayrepresent O or NH and R₁₀ may represent pyridyl, alkyl C 1 to C6 orhydrogen,

and pharmaceutically acceptable salts and solvates thereof.

According to the invention, there is also provided a process for thepreparation of compounds of formula I or pharmaceutically acceptablesalts or solvates thereof, which comprises removing a protecting groupfrom a corresponding compound of formula II, ##STR4## in which

R₃₀ a and R₄₀ a have the same significance, respectively, as R₃₀ andR₄₀, save that in addition one of R₃₀ a and R₄₀ a may represent a groupR_(a) 1, ##STR5## R₅₀ a has the same significance as R₅₀ above, savethat in addition it may represent R₃ a,

R₆₀ a has the same significance as R₆₀ above, save that in addition itmay represent a group R_(b) 1,

    CH.sub.2 XaCH.sub.2 Ya-CHR.sub.15 ZaR.sub.10 a             R.sub.b 1

in which

Xa and Za have the same significance, respectively, as X and Z above,save that in addition each may be substituted by OR₆ a,

Ya represents O, NR₄ a or NR₇₀ a,

R₇₀ a has the same significance as R₇₀ above, save that in addition itmay represent (CH₂)_(q) R₁₁ a,

R₁₀ a and R₁₁ a have, respectively, the same significance as R₁₀ and R₁₁above, save that when R₁₀ a or R₁₁ a represents phenyl, it may besubstituted by one or more substituents R₂₃ a,

R₁ a, R₂ a, R₃ a and R₄ a, which may be the same or different, representhydrogen or a protecting group,

R₂₀ a, R₂₁ a R₂₂ a and R₂₃ a, respectively, have the same significanceas R₂₀, R₂₁, R₂₂ and R₂₃ above, save that in addition they may representNR₂₅ R₂₇ a, SR₂₈ a, CH₂ OR₂₉ a or OR₃₁ a, wherein R₂₇ a, R₂₈ a, R₂₉ aand R₃₁ a, which may be the same or different, each represents aprotecting group, and R₁₅, R₂₅, m and q are as defined above, providedthat the compound of formula II bears at least one protecting group,

and where desired or necessary converting the resulting compound offormula I to a pharmaceutically acceptable salt or solvate thereof, orvice versa.

Protecting groups that R₁ a, R₂ a, R₃ a, R₄ a, R₂₇ a, R₂₈ a, R₂₉ a andR₃₁ a may represent include, for example, alkyl C 1 to 6, especiallymethyl; phenylalkyl C7 to 12, especially benzyl; alkanoyl C2 to 6, suchas acetyl and haloalkanoyl C2 to 6, especially trifluoroacetyl. Inaddition, the protecting group may protect two functional groups, forexample R2 and R3 may together represent ##STR6## Other protectinggroups are well known and include those described in Protective Groupsin Organic Chemistry, ed: J. W. F. McOmie, Plenum Press (1973), andProtective Groups in Organic Synthesis, T. W. Greene, Wiley-Interscience(1981).

Removal of the protecting group depends on the nature of the protectinggroup; conventional techniques may generally be employed, includingacidic or basic cleavage or hydrogenolysis. For example, protectingalkyl or phenylalkyl groups may be removed by cleavage using a proticacid, eg hydrochloric acid or a hydrobromic acid at a temperature offrom about 0° to 150° C., or a Lewis acid, eg by reacting with borontrihalide in a halocarbon solvent. 1-Phenylalkyl groups, eg benzyl, maybe removed by catalytic hydrogenation using a suitable catalyst, egpalladium, in a suitable solvent, eg methanol or acetic acid. Furthermethods for the removal of protecting groups are described in bothMcOmie and Greene, loc. cit. Both McOmie and Greene also describenumerous methods for the application of protecting groups.

Compounds of formula II in which X is interrupted by SO or SO₂ may bemade from the corresponding compounds of formula II in which X isinterrupted by S, by protection of the nitrogen atom(s) eg usingtrifluoracetic anhydride, oxidation, eg using m-chlorperbenzoic acid,and deprotection of the nitrogen atom(s).

Compounds of formula II in which R₆₀ a represents a group R_(b) 1 may bemade by reducing a corresponding compound of formula III, ##STR7## inwhich Q represents H₂ when Ya represents O, and O when Ya represents NR₄a or NR₇₀ a,

R₁ a, R₂ a, R₁₅, R₁₀ a, R₃₀ a, R₄₀ a, R₅₀ a, R₇₀ a, Xa, Ya and Za are asdefined above.

The reducing agent may be electrophilic, for example diborane, ornucleophilic, for example, a complex metal hydride such as lithiumaluminium hydride or sodium (2-methoxyethoxy)aluminium hydride. Thereaction may be carried out in a suitable solvent inert to the reactionconditions. Aprotic solvents are preferred, for example tetrahydrofuran,diethyl ether or 1,2-dimethoxyethane. The reaction may be carried out ata temperature of, for example, from 0° to 100° C.

Compounds of formula III, in which Ya represents NR₇₀ a or NR₄ a, may beprepared by condensing a compound of formula IV, ##STR8## in which R₃₅represents OH, and R₁ a, R₂ a, R₃₀ a, R₄₀ a, R₅₀ a and Xa are as definedabove, with a compound of formula V,

    HNR.sub.75 a CHR.sub.15 ZaR.sub.10 a                       V

in which R₇₅ a represents R₇₀ a or NR₄ a, and R₁₀ a, R₁₅, R₇₀ a and Zaare as defined above.

The condensation may be carried out under conditions similar to thoseused for the synthesis of peptide bonds in protein chemistry, e.g. bycarrying out the reaction in the presence of N,N'-carbonyldiimidazole ina polar aprotic solvent or using a hindered base, e.g. triethylamine andan alkyl chloroformate. The condensation may also be carried out byreacting the acid chloride of the compound of formula IV with thecompound of formula V.

Compounds of formula IV in which R₃₅ represents 0H may be prepared fromthe corresponding compound of formula IV in which R₃₅ represents alkoxyby hydrolysis, e.g. using sodium hydroxide in water.

Compounds of formula IV in which R₃₅ represents alkoxy may be preparedby condensing a compound of formula VI, ##STR9## in which R₁ a, R₂ a,R₃₀ a, R₄₀ a and R₅₀ a are as defined above, with a compound of formulaVII,

    HO.sub.2 CXaCOalkoxy                                       VII

in which Xa is as defined above.

The condensation may be carried out under conditions analogous to thosedescribed above for the preparation of compounds of formula III.

The compounds of formula III may also be prepared by condensing acompound of formula VI with a compound of formula VIII,

    HO.sub.2 CXaC(Q)YaCHR.sub.15 ZaR.sub.10 a                  VIII

in which Q, Xa, Ya, Za, R₁₀ a, R₁₅ and R₇₀ a are as defined above.

The condensation may be carried out under conditions analogous to thosedescribed above.

Compounds of formula II, in which one or both of R₅₀ a and R₆₀ arepresent alkyl C 1 to C6 may be prepared by conventional alkylation ofa compound of formula VI, in which R₅₀ a represents hydrogen or aprotecting group, ##STR10## in which R represents hydrogen or halogenand R₁ a, R₂ a and Ra are as defined above.

Esters of the benzoic acid IX may also be prepared by processesanalogous to the following route: ##STR11## in which R₁ a, R₂ a, R, R₂₀a, R₂₁ a and R₂₂ a are as defined above.

Other routes for the preparation of compounds of formula VI, in whichR₅₀ a represents hydrogen, are described in the Examples.

The compounds of formulae V, VII, VIII, X, XI and XII are either knownor may be made from known compounds using conventional techniques knownper se.

Acid addition salts of compounds of formula I may be converted to thecorresponding free-base by the action of a stronger base. The acidaddition salts of the compound of formula I may be prepared by reactionof the free base with an appropriate acid.

Pharmaceutically acceptable acid addition salts of the compounds offormula I include salts of mineral acids, for example, hydrohalic acids,e.g. hydrochloric or hydrobromic acid; or organic acids, e.g. formic,acetic or lactic acids. The acid may be polybasic, for examplesulphuric, fumaric or citric acid.

Solvates of the compounds of formula I and their salts include hydrates,in particular hydrates of the salts of formula I, e.g. hemihydrates,monohydrates and sesquihydrates.

We prefer compounds of formula I in which R₃₀ represents Ra.

We prefer compounds of formula I in which R₄₀ represents hydrogen.

We prefer compounds of formula I in which R₅₀ represents hydrogen andmore preferably compounds in which both R₅₀ and R₆₀ are hydrogen.

We prefer compounds of formula I in which R₁₀ represents phenylsubstituted by one or more substituents R₂₃. We prefer R10, when itrepresents phenyl, to be substituted by hydrogen or by one, two or threesubstituents other than hydrogen. Preferred groups that R₂₃ mayrepresent include hydrogen, halogen, e.g. fluorine or chlorine; hydroxy,NH₂, NHSO₂ alkyl C 1 to 6, NO₂ or alkyl C 1 to 6, eg methyl or ethyl. Weparticularly prefer compounds in which R₁₀ is substituted by one or morehydroxy groups, eg 4-OH. Groups that R₁₀ may particularly representinclude halodihydroxyphenyl, e.g. fluoro-dihydroxyphenyl;halohydroxyphenyl, e.g. fluorohydroxyphenyl; hydroxyphenyl, e.g. 3- or4-hydroxyphenyl; dihydroxyphenyl, e.g. 3,4-dihydroxyphenyl or2,3-dihydroxyphenyl.

When R₁₀ represents a saturated carbocyclic group, preferred carbocyclicgroups include those with 5 to 7 inclusive ring atoms, especially six,i.e. cyclohexyl.

When R₁₅ together with R₂₃ forms a chain, the group CHR₁₅ (CH₂)_(m-1)R₁₀ may represent 2-(1,2,3,4-tetrahydronaphthalenyl),1-(benzcyclobutenyl) or especially 2-indanyl.

Alkyl groups that R₁₀ may represent include methyl, ethyl, propyl orbutyl.

We prefer compounds of formula I in which R₂₀, R₂₁ and R₂₂ independentlyrepresent hydrogen, hydroxy, alkyl C 1 to 6, e.g. methyl or ethyl;halogen, e.g. chlorine or fluorine, or trifluoromethyl.

Compounds of formula I that may particularly be mentioned include thosein which at least one of R₂₀, R₂₁ and R₂₂ represents hydroxy. Weparticularly prefer compounds in which one of R₂₀, R₂₁ and R₂₂represents 3-hydroxy. Compounds that may also be specifically mentionedinclude those in which two of R₂₀, R₂₁ and R₂₂ represent hydroxy.

We prefer compounds of formula I in which X represents a C3 to C7, morepreferably a C4 to C6 inclusive alkylene chain.

We prefer compounds of formula I in which Y represents NH.

We prefer compounds of formula I in which 1 represents 2 or 3,especially 2.

We prefer compounds of formula I in which z represents (CH₂)₂ andespecially CH₂.

The compounds of formula I, and pharmaceutically acceptable acidaddition salts thereof, are useful because they possess pharmacologicalactivity in animals. Thus the compounds act on peripheral and/or centraldopamine receptors. As such, they lower blood pressure and increaseblood flow to certain vascular beds, e.g. renal beds. Activity of thecompounds has been investigated in the following assay systems:

(a) canine renal blood flow, McNay and Goldberg, J. Pharmac, Exp. Ther.,151, 23-31, 1966.

(b) rabbit isolated ear artery, McCullogh, Rand and Story, Br. J.Pharmac, 49, 141-142, 1973.

(c) guinea pig tracheal chains, Akcasu, Arch. Int. Pharmacodyn. Ther.,122, 201-207, 1959.

(d) guinea pig atria: O'Donnell and Wanstall, J. Pharm. Pharmacol., 31,686-690, 1979.

The compounds of the invention are indicated for use in the treatment ofcongestive heart failure, renal failure, angina pectoris, ischaemicheart disease and hypertension. The compounds of the invention are alsoindicated for use in the treatment of shock and other low cardiac outputstates of varying aetiology, acute cerebrovascular disease andimprovement of the blood supply to and healing of intestinal anastomosesand stomata.

The dosage administered will naturally depend on the compound employed,the mode of administration and the desired effect. However, in general,satisfactory results are obtained when the compound is administered at adosage of from 0.05 μg to 50mg per kilogram of body weight per day. Forman, the indicated total daily dosage is in the range 2.5 μg to 3.5 g,which may be administered in divided doses of, for example 1 μg to750mg.

The compounds of formula I, and pharmaceutically acceptable derivativesthereof, have the advantage that they are more efficacious or produceless undesirable side effects in certain pharmacological models thancompounds of similar structure to the compound of formula I.

The compound of the invention may be administered by a wide variety ofroutes and may act systemically or locally. Thus the compound may beadministered by oral or nasal inhalation to the lung, to the buccalcavity, oesophageally, rectally, topically to the skin or to otheravailable surfaces of the body, e.g. the eye, by injection, e.g.intravenously, intramuscularly, intraperitoneally, by installation or bysurgical implant.

According to our invention we also provide a pharmaceutical compositioncomprising preferably less than 80%, and more preferably less than 50%,by weight of a compound of formula I, or a pharmaceutically acceptablederivative thereof, in admixture with a pharmaceutically acceptableaduvant, diluent or carrier. Examples of suitable aduvants, diluents orcarriers are: for tablets, capsules and dragees; microcrystallinecellulose, calcium phosphate, diatomaceous earth, a sugar such aslactose, dextrose or mannitol, talc, stearic acid, starch, sodiumbicarbonate and/or gelatin;

for suppositories; natural or hardened oil or waxes; and

for inhalation compositions, coarse lactose.

When the compound is to be used in aqueous solution it may be necessaryto incorporate a chelating or sequestering agent, e.g. sodium edetate,an antioxidant, e.g. sodium metabisulphite or buffering agents, e.g.sodium hydrogen phosphate and sodium phosphate. Aqueous solutionstypically contain up to about 10% w/w of the new compound and may beused for intravenous injections.

According to the invention, we further provide a method of treatment ofacute renal failure in an animal, either human or non-human, whichmethod comprises administering to the animal an effective amount of thecompound of the invention or a pharmaceutically acceptable acid additionsalt thereof.

The invention is illustrated, but in no way limited, by the followingExamples in which temperatures are in degrees Centigrade.

A. PREPARATION OF INTERMEDIATES

1. Preparation of 4,4-dimethyloxazoles

(a) 2-[3,4-Dimethoxy-2-(2-[3-methoxyphenyl]ethyl)phenyl]-4,5-dihydro-4,4-dimethyloxazole

A solution of 2-(3-methoxyphenyl)ethylbromide (12.2 g) in drytetrahydrofuran (20 ml) was added dropwise to a suspension of magnesium(1.46 g) in dry tetrahydrofuran (20 ml), under an atmosphere ofnitrogen, at a rate sufficient to maintain a state of reflux. After 1hour the cooled solution was added to a stirred solution of4,5-dihydro-4,4-dimethyl-2-(2,3,4-trimethoxyphenyl) oxazole (7.95 g) indry tetrahydrofuran (50 ml) under an atmosphere of nitrogen. The mixturewas stirred at 20° for 16 hours. Water (400 ml) was added and theaqueous phase thoroughly extracted with ethyl acetate (2×250 ml). Theorganic phase was dried over magnesium sulphate, filtered and thesolvent removed in vacuo to yield a yellow oil which was purified byflash column chromatography on silica gel, using 10% ethyl acetate/90%petroleum ether as eluent, and by Kugelruhr distillation (air bathtemperature 200°/1 mm Hg) 9.7 g of the title compound were obtained msm/e 369.

The following oxazoles were prepared by the method of Intermediate 1(a):

(b)2-[3,4-Dimethoxy-2-[2-[3-methylphenyl]ethyl]phenyl]-4,5-dihydro-4,4-dimethyloxazole,m/e 353;

(c)2-[3,4-Dimethoxy-2-[2-[3-[trifluoromethyl]phenyl]ethyl]phenyl]-4,5-dihydro-4,4-dimethyloxazole,mp 63°-65°;

(d)2-[2-[2-[3-Chlorophenyl]ethyl]-3,4-dimethoxyphenyl]-4,5-dihydro-4,4-dimethyloxazole,mp 74°-76°;

(e)2-[3,4-Dimethoxy-2-[2-[3,5-dimethoxyphenyl]ethyl]phenyl]-4,5-dihydro-4,4-dimethyloxazole,m/e 399;

(f)2-[3,4-Dimethoxy-2-[3-[3-methoxyphenyl]propyl]phenyl]-4,5-dihydro-4,4-dimethyloxazole,m/e 383;

(g)2-[3,4-Dimethoxy-2-[4-[3-methoxyphenyl]butyl]phenyl]-4,5-dihydro-4,4-dimethyloxazole,m/e 397;

(h)2-[3,4-Dimethoxy-2-[2-[4-methoxyphenyl]ethyl]phenyl]-4,5-dihydro-4,4-dimethyloxazole,ms m/e 369;

(i)2-[3,4-Dimethoxy-2-[2-phenylethyl]phenyl]-4,5-dihydro4,4-dimethyloxazole,ms m/e 339;

(j)2-[3,4-Dimethoxy-2-[2-[3,4-dimethoxyphenyl]ethyl]phenyl]-4,5-dihydro-4,4-dimethyloxazole,ms m/e 399;

(k)2-[5-Chloro-3,4-dimethoxy-2-[2-[3-methoxyphenyl]ethyl]phenyl]-4,5-dihydro-4,4-dimethyloxazole,mp 95°-98°;

(l) 1)2-[5-Chloro-3,4-dimethoxy-2-[2-[4-methoxyphenyl]ethyl]phenyl]-4,5-dihydro-4,4-dimethyloxazole,m/e 403/405;

(m)2-[4,5-Dimethoxy-2-[2-[3-methoxyphenyl]ethyl]phenyl]-4,5-dihydro-4,4-dimethyloxazole,m/e 369.

2. Preparation of benzoic acids

(a) 3,4-Dimethoxy-2-[2-(3-methoxyphenyl)ethyl]benzoic acid

A solution of the product from Intermediate 1 (a) (9.7 g) in excessmethyl iodide (10 ml) was heated at reflux temperature for 4 hours. Dryether (100 ml) was added and the resulting precipitate filtered to yield11 g of the oxazolinium salt which was used without furtherpurification.

A solution of this oxazolinium salt (11 g) in 20% aqueous sodiumhydroxide (200 ml) and methanol (200 ml) was heated at refluxtemperature for 6 hours. The cooled solution was acidified and the solidfiltered, dried and crystallised from isopropanol to yield the titlecompound (6.2 g) as colourless prisms, mp 156°-158°.

Similarly prepared were:

(b) 3,4-Dimethoxy-2-[2-[3-methylphenyl]ethyl]benzoic acid, mp 150°-151°;

(c) 3,4-Dimethoxy-2-[2-[3-trifluoromethyl]phenyl]ethyl]benzoic acid, mp157°-159°;

(d) 2-[2-[3-Chlorophenyl]ethyl]-3,4-dimethoxybenzoic acid, mp 155°-156°;

(e) 2-[2-[3,5-Dimethoxyphenyl]ethyl]-3,4-dimethoxybenzoic acid, mp158°-160°;

(f) 3,4-Dimethoxy-2-[3-[3-methoxyphenyl]propyl]benzoic acid, mp127°-128°;

(g) 3,4-Dimethoxy-2-[4-[3-methoxyphenyl]butyl]benzoic acid, mp118°-119°;

(h) 3,4-Dimethoxy-2-[2-[4-methoxyphenyl]ethyl]benzoic acid, mp148°-150°;

(i) 3,4-Dimethoxy-2-[2-phenylethyl]benzoic acid, mp 142°-144°;

(j) 2-[2-[3,4-Dimethoxyphenyl]ethyl]-3,4-dimethoxy benzoic acid, mp148°-149°;

(k) 5-Chloro-3,4-dimethoxy-2-[2-[3-methoxyphenyl]ethyl]benzoic acid, mp123°-125°;

(l) 5-Chloro-3,4-dimethoxy-2-[2-[4-methoxyphenyl]ethyl]benzoic acid, mp96°-98°;

(m) 4,5-Dimethoxy-2-[2-[3-methoxyphenyl]ethyl]benzoic acid, mp152°-155°.

3. Preparation of benzene methanols

Method A

(a) 3,4-Dimethoxy-2-[2-(methoxyphenyl)ethyl]benzene methanol

A solution of the product from Intermediate 2 (a) (6.2 g) in drytetrahydrofuran (50 ml) was stirred under an atmosphere of nitrogenduring the addition of 40 ml of a 1M solution of borane intetrahydrofuran complex. The mixture was heated under reflux for 3hours, cooled and methanol (80 ml) added. The solution was evaporated todryness, dissolved in ethyl acetate and washed with 2N hydrochloricacid, saturated sodium bicarbonate solution and brine. The organic phasewas dried (MgSO₄), filtered and the solvent removed in vacuo to leave asolid which was crystallised from isopropanol to yield 5.2 g of thetitle compound as colourless flakes, mp 108°-109°.

Similarly prepared were:

(b) 3,4-Dimethoxy-2-[2-[3-methylphenyl]ethyl]benzenemethanol, mp81°-83°;

(c) 3,4-Dimethoxy-2-[2-[3-trifluoromethyl]phenyl]ethyl]benzenemethanol,mp 123°-125°;

(d) 2-[2-[3-Chlorophenyl]ethyl]-3,4-dimethoxy benzenemethanol, mp129°-131°;

(e) 2-[2-[3,5-Dimethoxyphenyl]ethyl]-3,4-dimethoxy benzenemethanol, mp125°-126°;

(f) 3,4-Dimethoxy-2-[3-[3-methoxyphenyl]propyl] benzenemethanol, mp62.5°-63.5°;

(g) 3,4-Dimethoxy-2-[4-[3-methoxyphenyl]butyl]benzenemethanol, mp54°-56°;

(h) 3,4-Dimethoxy-2-[2-[4-methoxyphenyl]ethyl]benzenemethanol, mp83°-85°;

(i) 3,4-Dimethoxy-2-[2-phenylethyl]benzenemethanol, mp 99°-100°;

(j) 2-[2-[3,4-Dimethoxyphenyl]ethyl]3,4-dimethoxy benzenemethanol, mp103.5°-105.5;

(k) N-[3-[2-[2,3,-Dimethoxy-6hydroxymethylphenyl]ethyl]phenyl]methanesulphonamide, mp 113°-115°;

(l) 5-Chloro-3,4-dimethoxy-2-[2-[3-methoxyphenyl]ethyl]benzenemethanol,mp 54°-56°;

(m) 5-Chloro-3,4-dimethoxy-2-[2-[4-methoxyphenyl]ethyl]benzenemethanol,m/e 408;

(n) 4,5-Dimethoxy-2-[2-[3-methoxyphenyl]ethyl]benzenemethanol, m/e 302.

Method B

(a) 2-[2-[3,5-Dimethoxyphenyl]ethyl]3,4-dimethoxybenzene methanol

A 1M solution of lithium aluminium hydride in tetrahydrofuran (80 ml)was added dropwise to a stirred solution of the intermediate ester fromstep 15Bb (20 g) in dry tetrahydrofuran under a nitrogen atmosphere at-78°. The solution was stirred at 20° for 2 hours. The mixture wasquenched with brine (10 ml) and evaporated to dryness. The residue waspartitioned between ether and 2N hydrochloric acid and separated. Theorganic solution was washed with brine, dried (MgSO₄), filtered andevaporated to give a solid. Crystallisation from isopropanol gave 15 gof the intermediate alcohol as colourless flakes, mp 126°-128°.

Similarly prepared were:

(b) 3,4-Dimethoxy-2-[2-[3,4,5-trimethoxyphenyl]ethyl]benzenemethanol, mp132.5°-134°;

(c) 3,4-Dimethoxy-5-[2-[3-methoxyphenyl]ethyl]benzenemethanol, m/e 302.

Method C

(a) E-3,4-Dimethoxy-2-[2-[3,4,5-trimethoxyphenyl]ethenyl]benzenemethanol

A 1.5M solution of diisobutylaluminium hydride in toluene (50 ml) wasadded dropwise to a stirred solution of the ethenyl ester from step15Bal (14.6 g) in dry tetrahydrofuran (120 ml). The solution was stirredat 20° for 11/2 hours. The solution was evaporated and the residuequenched slowly with 2N hydrochloric acid and extracted with ethylacetate. The organic solution was washed with brine, dried (MgSO₄),filtered and evaporated to give a solid which crystallised fromisopropanol to give 9.64 g of the alcohol as colourless flakes, mp119.5°-121°.

Method D

(a) 3,4-Dimethoxy-2-[2-[3-nitrophenyl]ethyl]benzenemethanol

A 0.5M solution of Aluminium hydride in tetrahydrofuran (56 ml) wasadded dropwise to a solution of the intermediate 15BC (5.06 g) in drytetrahydrofuran (50 ml). The solution was stirred at 20° for 16 hours.The solution was quenched with water and extracted with ethyl acetate.The organic phase was dried (MgSO₄), filtered and evaporated. Theresidue was purified by flash chromatography (Merck 9385 silica gel)eluting with ethyl acetate/60/80 petrol ether (1:1) to give the alcoholas a colourless solid (3.21 g).

4. Preparation of benzeneacetonitriles

Method A

(a) 3,4-Dimethoxy-2-[2-(3-methoxyphenyl)ethyl]benzeneacetonitrile

A solution of the alcohol from Intermediate 3 (a) (5 g) and thionylchloride (1.5 ml) in dry dichloromethane (50 ml) was heated at refluxtemperature for 3 hours. The solution was evaporated to dryness.

The cooled crude chloride was dissolved in dry dimethylsulphoxide (25ml). Powdered sodium cyanide (1.5 g) was added to the solution and themixture was stirred at 20° for 16 hours. Brine (150 ml) was added andthe mixture extracted with ethyl acetate. The organic phase was washedwith brine, dried over magnesium sulphate, filtered and evaporated on asteam bath until HCN had ceased to be evolved. Further evaporation gavea yellow solid which was crystallised from isopropanol to yield 4.0 g ofthe title compound as prisms, mp 98°-100°.

Similarly prepared were:

(b) 3,4-Dimethoxy-2-[2-[3-methylphenyl]ethyl]benzeneacetonitrile, mp87°-88°;

(c)3,4-Dimethoxy-2[2-[3-[trifluoromethyl]phenyl]ethyl]benzeneacetonitrile,mp 84°-85°;

(d) 2-[2-[3-Chlorophenyl]ethyl]-3,4-dimethoxy benzeneacetonitrile, mp71.5°-73.5°;

(e) 3,4-Dimethoxy-2-[2-[4-methoxyphenyl]ethyl]benzeneacetonitrile, mp91°-93°;

(f) 3,4-Dimethoxy-2-[2-phenylethyl]benzeneacetonitrile, ms m/e 287;

(g)E-3,4-Dimethoxy-2-[2-[3,4,5-trimethoxyphenyl]ethenyl]benzeneacetonitrile,mp 134°-136°;

(h) 3,4-Dimethoxy-2-[2-[3-nitrophenyl]ethyl]benzeneacetonitrile, mp112°-115°;

(i) N-[3-[2-[2,3-Dimethoxy-6-cyanomethylphenyl]ethyl]phenyl]methanesulphonamide, mp 111°-112°;

(j) 5-Chloro-3,4-dimethoxy-2-[2-[3-methoxyphenyl]ethyl]benzeneacetonitrile, mp 70°-72°;

(k)5-Chloro-3,4-dimethoxy-2-[2-[4-methoxyphenyl]ethyl]benzeneacetonitrile,mp 95°-96°;

(l) 4,5-Dimethoxy-2-[2-[3-methoxyphenyl]ethyl]benzeneacetonitrile, mp71°-73°;

(m) 3,4-Dimethoxy-5-[2-[3-methoxyphenyl]ethyl]benzeneacetonitrile, m/e311.

Method B

(a) 3,4-Dimethoxy-2-[3-[3-methoxyphenyl]propyl]benzeneacetonitrile

Methanesulphonylchloride (1.8 ml) was added to a cooled (-10°) stirredsolution of the alcohol Intermediate 3 f) (6.5 g), triethylamine (4 ml),4-N,N-dimethylaminopyridine (5mg) in dry dichloromethane (50 ml). Themixture was stirred at room temperature under a nitrogen atmosphere for2 hours. The solution was then washed with 2N hydrochloric acid,saturated sodium bicarbonate solution, brine, dried (MgSO₄), filteredand evaporated to leave the chloride as a yellow oil.

Powdered sodium cyanide (2 g) was added to a stirred solution of thechloride in dry dimethylsulphoxide (20 ml). The solution was stirred atroom temperature for 16 hours. Brine (100 ml) was added and the mixtureextracted with ethyl acetate. The organic phase was washed with brine,dried (MgSO₄), filtered and evaporated on a steam bath until HCN hadceased to be evolved. Further evaporation gave a solid which waspurified by column chromatography (CH₂ Cl₂ :60/80 Petrol 1:2) as eluantand the recovered solid crystallised three times from isopropanol (3.95g) to give the title compound, mp 78°-79°.

Similarly prepared were:

(b) 2-[2-[3,5-Dimethoxyphenyl]ethyl]-3,4-dimethoxy benzeneacetonitrile,m/e 341;

(c) 3,4-Dimethoxy-2-[4-[3-methoxyphenyl]butyl]benzeneacetonitrile, m/e339;

5. Preparation of intermediates of formula VI in which R₅₀ a is hydrogen

(a) 3,4-Dimethoxy-2-[2-[3-methoxyphenyl]ethyl]benzeneethanaminehydrochloride

A solution of the nitrile from Intermediate 4 (a) (4 g) in drytetrahydrofuran (50 ml) was stirred under an atmosphere of nitrogenduring the addition of a 1M solution of borane in tetrahydrofuran (25.7ml). The mixture was heated at reflux temperature for 2 hours. Methanol(40 ml) was added to the cooled reaction mixture and the solutionevaporated to dryness. The residue was dissolved in methanol (50 ml) andconc. hydrochloric acid (5 ml) added. The mixture was heated at refluxtemperature for 1 hour and then the solution was evaporated to drynessto yield a beige solid. This was treated with dilute sodium hydroxidesolution to yield3,4-dimethoxy-2[2-(3-methoxyphenyl)ethyl]-benzeneethanamine which waspurified by flash column chromatography on silica gel using 90%chloroform/10% methanol as eluent. The resulting oil was treated withethereal HCl to give 1.2 g of the title compound as colourless prismsafter crystallisation from isopropanol, mp 164°-166°.

Similarly prepared were:

(b) 3,4-Dimethoxy-2-[2-[3-methylphenyl]ethyl]benzeneethanaminehydrochloride, mp 165.5°-166.5°;

(c)3,4-Dimethoxy-2-[2-[3-[trifluoromethyl]phenyl]ethyl]benzeneethanaminehydrochloride hydrate, mp 188°-190°;

(d) 2-[2-[3-Chlorophenyl]ethyl]-3,4-dimethoxy benzeneethanamainehydrochloride, mp 179°-181°;

(e) 2-[2-[3,5-Dimethoxyphenyl]ethyl]-3,4-dimethoxy benzeneethanaminehydrochloride, mp 179°-180°;

(f) 3,4-Dimethoxy-2-[3-[3-methoxyphenyl]propyl]benzeneethanaminehydrochloride, mp 88°-90°;

(g) 3,4-Dimethoxy-2-[4-[3-methoxyphenyl]butyl]benzeneethanaminehydrochloride, oil;

(h) 3,4-Dimethoxy-2-[2-[4-methoxyphenyl]ethyl]benzeneethanaminehydrochloride, mp 135°-137°;

(i) 3,4-Dimethoxy-2-[2-phenylethyl]benzeneethanamine hydrochloride, mp201°-203°;

(j) 3,4-Dimethoxy-2-[2-[3,4,5-trimethoxyphenyl]ethyl]benzeneethanaminehydrochloride, softens 105°-110°, mp 158.5°-159.5°;

(k) 3,4-Dimethoxy-2-[2-[3-nitrophenyl]ethyl]benzeneethanaminehydrochloride, mp 228°-230°;

(l) N-[3-[2-[2,3-Dimethoxy-6-[2-aminoethyl]phenyl]ethyl]phenyl]methanesulphonamide hydrochloride, mp181°-183°;

(m) 5-Chloro-3,4-dimethoxy-2-[2-[3-methoxyphenyl]ethyl]benzeneethanaminehydrochloride, mp 147°-149°;

(n) 5-Chloro-3,4-dimethoxy-2-[2-[4-methoxyphenyl]ethyl]benzeneethanaminehydrochloride, mp 197°-199°;

(o) 4,5-Dimethoxy-2-[2-[3-methoxyphenyl]ethyl]benzeneethanaminehydrochloride, mp 178°-179°;

(p) 3,4-Dimethoxy-5-[2-[3-methoxyphenyl]ethyl]benzeneethanaminehydrochloride, m/e 315.

6. Preparation of diamide intermediates of formula III fromintermediates of formula VI and intermediates of formula VIII

(a)N-[2-[3,4-Dimethoxy-2-[2-[3-methoxyphenyl]ethyl]phenyl]ethyl]-N'-[2-phenylethyl]hexane-1,6-diamide

A solution of 6-oxo-6-(2-phenylethylamino)hexanoic acid (1.2 g) andN,N'-carbonyldiimidazole (0.77 g) in dry dichloromethane (50 ml) wasstirred at 20° for 2 hours and a solution of3,4-dimethoxy-2-[2-[3-methoxyphenyl] ethyl]benzeneethanamine (1.5 g) indry dichloromethane (10 ml) was added. The mixture was stirred at 20°for 16 hours. Water (50 ml) was added and the organic phase wasseparated and washed with 2N hydrochloric acid, aqueous sodiumbicarbonate and brine. The organic phase was dried (MgSO₄), filtered andthe solvent removed in vacuo. The resulting solid was crystallised fromisopropanol to yield 2.1 g of the sub-title compound as colourlessprisms, mp 150°-151°.

Similarly prepared were:

(b)N-[2-[3,4-Dimethoxy-2-[2-[3-methoxyphenyl]ethyl]phenyl]ethyl]-N'-[2-phenylethyl]butane-1,4-diamide,mp 157°-158°;

(c)N-[2-[3,4-Dimethoxy-2-[2-[3-methoxyphenyl]ethyl]phenyl]ethyl]-N'-[2-phenylethyl]octane-1,8-diamide,mp 131°-133°;

(d)N-[2-Cyclohexylethyl]-N'-[2-[3,4-dimethoxy-2-[2-[3methoxyphenyl]ethyl]phenyl]ethyl]hexane-1,6-diamide,mp 136.5°-137.5°;

(e)N-[2-[3,4-Dimethoxy-2-[2-[3-[trifluoromethyl]phenyl]ethyl]phenyl]ethyl]-N'-[2-phenylethyl]hexane-1,6-diamide,mp 165°-166°;

(f)N-[2-[3,4-Dimethoxy-2-[2-[3-methylphenyl]ethyl]phenyl]ethyl]-N'-[2-phenylethyl]hexane-1,6-diamide,mp 169°-170°;

(g) N-[2-[3,4-Dimethoxy-2-[2-[3-methylphenyl]ethyl]phenyl]ethyl]-N'-[2-[4-methoxyphenyl]ethyl]hexane-1,6-diamide, mp 265°-267°;

(h)N-[2-[3,4-Dimethoxy-2-[3-[3-methoxyphenyl]propyl]phenyl]ethyl]-N'-[2-phenylethyl]hexane-1,6-diamide,mp 125°-126°;

(i)N-[2-[3,4-Dimethoxy-2-[3-[3-methoxyphenyl]propyl]phenyl]ethyl]-N'-[2-[4-methoxyphenyl]ethyl]hexane-1,6diamide,mp 145.5°-147.5°;

(j)N-[2-[3,4-Dimethoxy-2-[2-[3,5-dimethoxyphenyl]ethyl]phenyl]ethyl]-N'-[2-phenylethyl]hexane-1,6-diamide,mp 167°-169°;

(k)N-[2-[2-[2-[3-Chlorophenyl]ethyl]-3,4-dimethoxyphenyl]ethyl]-N'-[2-phenylethyl]hexane-1,6-diamide,mp 169°-170°;

(l)N-[2-[2-[2-[3-Chlorophenyl]ethyl]-3,4-dimethoxyphenyl]ethyl]-N'-[2-[4-methoxyphenyl]ethyl]hexane-1,6-diamide,mp 164°-166°;

(m)N-[2-Cyclohexylethyl]-N'-[2-[3,4-dimethoxy-2-[2-[4-methoxyphenyl]ethyl]phenyl]ethyl]hexane-1,6-diamide,mp 140.5°-143°;

(n)N-[2-[3,4-Dimethoxy-2-[2-[4-methoxyphenyl]ethyl]phenyl]ethyl]-N'-[2-[4-methoxyphenyl]ethyl]hexane-1,6diamide,mp 159°-160°;

(o)N-[2-[3,4-Dimethoxy-2-[4-[3-methoxyphenyl]butyl]phenyl]ethyl]-N'-[2-phenylethyl]hexane-1,6-diamide,mp 123°-125°;

(p)N-[2-[3,4-Dimethoxy-2-[2-[3-methoxyphenyl]ethyl]phenyl]ethyl]-N'-[2-[3,4-dimethoxyphenyl]ethyl]hexane-1,6diamide,mp 141°-143°;

(q)N-[2-[3,4-Dimethoxy-2-[2-[3-methoxyphenyl]ethyl]phenyl]ethyl]-N'-[2-[4-methoxyphenyl]ethyl]octane-1,8diamide,mp 137°-139°;

(r)N-[2-[3,4-Dimethoxy-2-[2-[3-methoxyphenyl]ethyl]phenyl]ethyl]-N'-[2-[3-methoxyphenyl]ethyl]hexane-1,6-diamide,mp 131°-132°;

(s)N-[2-[3,4-Dimethoxy-2-[2-[3-methoxyphenyl]ethyl]phenyl]ethyl]-N'-[2-[4-methylphenyl]hexane-1,6-diamide,mp 157°-158°;

(t)N-[2-[3,4-Dimethoxy-2-[2-[3-methoxyphenyl]ethyl]phenyl]ethyl]-N'-[2-[2,3-dimethoxyphenyl]ethyl]hexane-1,6diamide,mp 134°-135°;

(u)N-[2-[3,4-Dimethoxy-2-[2-[3-methoxyphenyl]ethyl]phenyl]ethyl]-N'-hexyl-hexane-1,6-diamide,mp 127°-128°;

(v)N-[2-[3,4-Dimethoxy-2-[2-[3-methoxyphenyl]ethyl]phenyl]ethyl]-N'-[2-[2-fluoro-3,4-dimethoxyphenyl]ethyl]hexane-1,6-diamide,mp 140°-141°;

(w)N-[2-[3,4-Dimethoxy-2-[2-[3-methoxyphenyl]ethyl]phenyl]ethyl]-N'-[2-[3-fluoro-4-methoxyphenyl]ethyl]hexane-1,6-diamide,mp 147°-149°;

(x)E-N-[2-[3,4-Dimethoxy-2-[2-[3-methoxyphenyl]ethyl]phenyl]ethyl]-N'-[2-phenylethyl]-3-hexene-1,6-diamide,mp 131°-133°;

(y)N-[2-[3,4-Dimethoxy-2-[2-[3-methoxyphenyl]ethylphenyl]ethyl]-N'-[2-phenylethyl]heptane-1,7-diamide,mp 103°-108°;

(z)N-[2-[3,4-Dimethoxy-2-[2-[3-methoxyphenyl]ethyl]phenyl]ethyl]-N'-[2-phenylethyl]nonane-1,9-diamide,mp 116°-118°;

(aa)N-[2-[3,4-Dimethoxy-2-[2-[3-methoxyphenyl]ethyl]phenyl]ethyl]-N'-[2-phenylethyl]decane-1,10-diamide,mp 133°-135°;

(bb)N-[2-[3,4-Dimethoxy-2-[2-[3-methoxyphenyl]ethyl]phenyl]ethyl]-N'-[2-phenylethyl]-3-methylpentane-1,5-diamide,softens 112°, mp 133°-135°;

(cc)N-[2-[3,4-Dimethoxy-2-[2-[3-methoxyphenyl]ethyl]phenyl]ethyl]-N'-[2-phenylethyl]-3,3-dimethylpentane-1,5-diamide,ms m/e 560;

(dd)N-[2-[3,4-Dimethoxy-2-[2-[3-methoxyphenyl]ethyl]phenyl]ethyl]-N'-[2-phenylethyl]pentane-1,5-diamide,mp 132°-134°;

(ee)N-[2-[5-Chloro-3,4-dimethoxy-2-[2-[3-methoxyphenyl]ethyl]phenyl]ethyl]-N'-[2-phenylethyl]hexane-1,6-diamide,mp 145°-147°;

(ff)N-[2-[5-Chloro-3,4-dimethoxy-2-[2-[4-methoxyphenyl]ethyl]phenyl]ethyl]-N'-[2-phenylethyl]hexane-1,6-diamide,mp 135°-137°;

(gg)N-[2-[3,4-Dimethoxy-5-[2-[3-methoxyphenyl]ethyl]phenyl]ethyl]-N'-[2-phenylethyl]hexane-1,6-diamide,mp 122°-124°;

(hh)N-[2-[4,5-Dimethoxy-2-[2-[3-methoxyphenyl]ethyl]phenyl]ethyl]-N'-[2-phenylethyl]hexane-1,6-diamide,mp 135°-136°;

(ii)N-[2-[3,4-Dimethoxy-2-[2-[3-methoxyphenyl]ethyl]phenyl]ethyl]-N'-methyl-N'-[2-phenylethyl]hexane-1,6-diamide,oil, m/e 560;

(jj)N-[2-[3,4-Dimethoxy-2-[2-[3-methoxyphenyl]ethyl]phenyl]ethyl]-N'-N'-di[2-phenylethyl]hexane-1,6-diamide,mp 97°-99°;

(kk)N-[2-[3,4-Dimethoxy-2-[2-[3-methoxyphenyl]ethyl]phenyl]ethyl]-N'-[2-[4-methoxyphenyl]ethyl]-N'-[2-phenylethyl]hexane-1,6-diamide,oil, m/e 681.

7. Preparation of intermediates of formula IV from intermediates offormula VI and intermediates of formula VII

(a)6-[2-[3,4-Dimethoxy-2-[2-[3-methoxyphenyl]ethyl]phenyl]ethylamino]-6-oxohexanoic acid

Methyl 5-[chloroformyl]pentanoate (5.5 g) in dry dichloromethane (20 ml)was added dropwise to a stirred and cooled (-5° to 0°) solution of3,4-dimethoxy[2-[2-[3-methoxyphenyl]ethyl]benzeneethanamine (9.64 g) andtriethylamine (4.27 ml) in dry dichloromethane (150 ml). The resultingmixture was stirred at room temperature for 16 hours. The reactionmixture was washed with 2N hydrochloric acid (50 ml), 10% aqueous sodiumbicarbonate solution (50 ml), water (50 ml), dried (MgSO₄), andevaporated in vacuo affording the crude amido ester (14 g). A solutionof the amido ester in methanol (125 ml) was treated with a solution ofsodium hydroxide (1.35 g) in water (13.5 ml) and the mixture heated atreflux temperature for 3 hours. The cooled reaction mixture wasacidified with 2N hydrochloric acid and extracted with chloroform (2×200ml). The organic phase was separated, dried (MgSO₄), filtered andevaporated to leave the title compound as a solid which crystallisedfrom isopropanol as prisms (10.5 g), mp 119°-121°.

(b)3-[2-[3,4-Dimethoxy-2-[2-[3-methoxyphenyl]ethyl]phenyl]ethylamino]-3-oxo-propylthioaceticacid

A solution of 3-[methoxycarbonylmethylthio]propionic acid (1.97 g) andN,N'-carbonyldiimidazole (1.1 g) in dry dichloromethane (50 ml) wasstirred under a nitrogen atmosphere for 1.5 hours. A solution of3,4-dimethoxy-2-[2-[3-methoxyphenyl]ethyl]benzeneethanamine (3.49 g) indry dichloromethane (40 ml) was added and the mixture stirred for 18hours.

The solution was washed with 2N hydrochloric acid (100 ml), saturatedsodium bicarbonate solution (100 ml) and brine (100 ml), dried (MgSO₄),filtered and evaporated to leave a dark brown oil. This oil waspartially purified by flash chromatography (Merck 9385 silica gel)eluting with ether. Evaporation gave the methyl ester of the sub-titleacid as an orange oil (2.43 g).

A solution of this oil in methanol (30 ml) was treated with water (7 ml)and saturated sodium bicarbonate solution (15 ml) and the mixture heatedto reflux temperature under a nitrogen atmosphere for 3 hours. Themajority of the methanol was removed in vacuo and the aqueous solutionacidified and extracted with ether (3×50 ml). The organic phase wasdried (MgSO₄), filtered and evaporated to give the title acid as aviscous yellow oil (1.92 g), MS M⁺ m/e 461.

8 Preparation of intermediates of formula III from intermediates offormula IV and formula V

(a)N-[2-[3,4-Dimethoxy-2-[2-[3-methoxyphenyl]ethyl]phenyl]ethyl]-N'-[2-[4-methoxyphenyl]ethyl]hexane-1,6-diamide

A solution of the product from Intermediate 7 (a) (2.09 g) andN,N-carbonyldiimidazole (0.77 g) in dry dichloromethane (100 ml) wasstirred at 20° C. for 3 hours and a solution of4-methoxybenzeneethanamine (0.72 g) in dry dichloromethane (10 ml) wasthen added. The mixture was stirred at 20° for 17 hours.

The solution was quenched with water (30 ml) and chloroform (100 ml)added. The organic phase was separated, dried (MgSO₄), filtered andevaporated to leave a solid which crystallised from isopropanol to givethe title compound as a white solid 1.88 g, mp 153°-155°.

Similarly prepared were:

(b)N-[2-[4-Chlorophenyl]ethyl]-N'-[2-[3,4-dimethoxy-2-[2-[3-methoxyphenyl]ethyl]phenyl]ethyl]hexane-1,6-diamide,mp 150°-152°;

(c)N-[2,3-Dihydro-1H-indene-2-yl]-N'-[2-[3,4-dimethoxy-2-[2-[3-methoxyphenyl]ethyl]phenyl]ethyl]hexane-1,6-diamide,mp 161°-162°;

(d)N-[2-[3,4-Dimethoxy-2-[2-[3-methoxyphenyl]ethyl]phenyl]ethyl]-N'-[2-[4-nitrophenyl]ethyl]hexane-1,6diamide,mp 128°-129°;

(e)N-[2-[3,4-Dimethoxy-2-[2-[3-methoxyphenyl]ethyl]phenyl]ethyl]-N'-[2-[4-pyridyl]ethyl]hexane-1,6-diamide,mp 138°-141°;

(f)N-[2-[3,4-Dimethoxy-2-[2-[3-methoxyphenyl]ethyl]phenyl]ethyl]-3-[2-oxo-2-[2-phenylethylamino]ethylthio]propanamide,as flakes from acetonitrile, mp 116°-118°.

9. Preparation of intermediates of formula VIII

(a) 6-(2-Cyclohexylethylamino)-6-oxohexanoic acid

Methyl 5-[chloroformyl]pentanoate (4.2 g) in dry dichloromethane (20 ml)was added dropwise to a stirred solution of 2-cyclohexylethylamine (3 g)and triethylamine (3.3 ml) in dry dichloromethane (40 ml) under a N₂atmosphere. The mixture was stirred at room temperature for 16 hours andheated under reflux for 1.5 hours.

The cooled solution was washed with 2N hydrochloric acid, saturatedbicarbonate solution and brine. The organic solution was dried (MgSO₄),filtered and evaporated to leave the ester as a yellow oil (6.3 g).

A solution of the ester in methanol (50 ml) and 10% sodium hydroxidesolution (10 ml) was heated under reflux for 3 hours. The solution wasevaporated to half volume and acidified with 2N hydrochloric acid. Theprecipitate was extracted with ethyl acetate and the solution dried(MgSO₄), filtered and evaporated. Crystallisation from ethyl acetategave the title acid as a colourless solid (3 g), mp 95°-96°.

Similarly prepared were:

(b) 8-[2-[4-Methoxyphenyl]ethylamino]-8-oxooctanoic acid, mp125.1°-125.9°;

(c) 6-[2-[3-Methoxyphenyl]ethylamino]-6-oxohexanoic acid, mp 96°-98°;

(d) 6-[2-[4-Methylphenyl]ethylamino]-6-oxohexanoic acid, mp 143°-144°;

(e) 6-Hexylamino-6-oxohexanoic acid, mp 95°-96°;

(f) 6-[2-[3-Fluoro-4-methoxyphenyl]ethylamino]-6oxohexanoic acid, mp118°-120°;

(g) 6-[2-[2-Fluoro-3,4-dimethoxyphenyl]ethylamino]-6oxohexanoic acid, mp95°-97°;

(h) 6-[2-[2,3-Dimethoxyphenyl]ethylamino]-6-oxohexanoic acid, m/e 309.

(i) 6-Oxo-6-[2-phenylethylamino]-3,E-hexenoic acid

Ethylchloroformate (11.25 ml) was added to a stirred solution of trans3-hexenedioc acid (16.93 g) and triethylamine (16.35 ml) in drychloroform (170 ml) at -5° under a N₂ atmosphere. The solution wasstirred for 30 minutes then a solution of 2-phenylethylamine (14.78 ml)in dry chloroform (50 ml) was added. The reaction mixture was stirred atroom temperature for 3 hours. The solution was washed with 2Nhydrochloric acid, saturated sodium bicarbonate solution, brine, dried(MgSO₄), filtered and evaporated to leave the title compound as a solidwhich crystallised from isopropanol (8.73 g), mp 101°-103°.

(j) 7-Oxo-7-[2-phenylethylamino]heptanoic acid

A solution of monomethylpimelate (5.0 g) and N,N-carbonyldiimidazole(4.9 g) in dry dichloromethane (200 ml) was stirred under nitrogen at20° for 2 hours and a solution of 2-phenylethylamine (3.22 g) in drydichloromethane (100 ml) was then added. The mixture was stirred at 20°for 16 hours. The solution was quenched with 2N hydrochloric acid (50ml) and separated. The organic solution was washed with water, dried(MgSO₄), filtered and evaporated to leave the intermediate ester as asolid (7.05 g).

A solution of the ester (7.0 g) in methanol (100 ml) and 20% sodiumhydroxide solution (15 ml) was heated to reflux temperature for 3 hours.The solution was evaporated and the residue acidified with 2Nhydrochloric acid. The solid mass was dissolved in ethyl acetate (400ml), washed with water (2×100 ml), dried (MgSO₄), filtered andevaporated. Crystallisation from ethyl acetate gave the sub-title acidintermediate as colourless prisms (5.7 g), mp 78°-79°.

Similarly prepared were:

(k) 9-Oxo-9-[2-phenylethylamino]nonanoic acid, mp 97.5°--99°;

(l) 10-Oxo-10-[2-phenylethylamino]decanoic acid, mp 108.5°-109.5°;

(m) 6-Oxo-6-[N-methyl-N-2-phenylethylamino]hexanoic acid, mp 95°-97°;

(n) 6-Oxo-6-[[N-2-phenylethyl]-2-phenylethylamino]hexanoic acid, m/e353;

(o) 6-Oxo-6-[[N-2-[4-methoxyphenyl]ethyl]-2phenylethylamino]hexanoicacid, m/e 383;

(p) 3-Methyl-5-oxo-5-[2-phenylethylamino]pentanoic acid

A solution of 2-phenylethylamine (6.3 ml) in dry toluene (50 ml) wasadded dropwise to a stirred solution of 3-methylglutaric anhydride (6.4g) in dry toluene (250 ml) at 0° under a nitrogen atmosphere. Aftercomplete addition the mixture was heated at reflux temperature for 3hours. The solution was evaporated and the residual oil triturated withether (150 ml). The solid was filtered and dried to give the sub-titleintermediate (3.3 g), mp 78°-80°.

Similarly prepared were:

(q) 3,3-Dimethyl-5-oxo-5-[2-phenylethylamino]pentanoic acid, ms m/e 263;

(r) 5-Oxo-5-[2-phenylethylamino]pentanoic acid, mp 83.5°-85°.

10. Preparation of intermediates of formula II

(a)N-[2-[3,4-Dimethoxy-2-[2-[3-methoxyphenyl]ethyl]phenyl]ethyl]-N'-[2-phenylethyl]hexane-1,6-diaminedihydrochloride

A solution of the product from Intermediate 6 (a) (1.8 g) in drytetrahydrofuran (80 ml) was stirred under an atmosphere of nitrogenduring the addition of a 1M solution of borane in tetrahydrofuran (16ml). The mixture was heated at reflux temperature for 4 hours and thenstirred at 20° for 16 hours. Methanol (50 ml) was added to the cooledsolution and the mixture evaporated to dryness. The residue wasdissolved in methanol (50 ml) and concentrated hydrochloric acid (5 ml)added. The mixture was heated at reflux temperature for 1 hour. Thesolution was evaporated to give a solid which was crystallised fromethanol to yield 1.6 g of the dihydrochloride salt of the title compoundas colourless prisms, mp 229°-231°.

Similarly prepared were:

(b)N-[2-[3,4-Dimethoxy-2-[2-[3-methoxyphenyl]ethyl]phenyl]ethyl]-N'-[2-phenylethyl]butane-1,4-diaminedihydrochloride, mp 213°-215°;

(c)N-[2-[3,4-Dimethoxy-2-[2-[3-methoxyphenyl]ethyl]phenyl]ethyl]-N'-[2-phenylethyl]octane-1,8-diaminedihydrochloride, mp 219°-220°;

(d)N-[2-[3,4-Dimethoxy-2-[2-[3-methoxyphenyl]ethyl]phenyl]ethyl]-N'-[2-[4-methoxyphenyl]ethyl]hexane-1,6-diaminedihydrochloride, mp 223°-226°;

(e)N-[2-[4-Chlorophenyl]ethyl]-N'-[2-[3,4-dimethoxy-2-[2-[3-methoxyphenyl]ethyl]phenyl]ethyl]hexane-1,6-diaminedihydrochloride, mp 225°-227°;

(f)N-[2,3-Dihydro-1H-indene-2-yl]-N'-[2-[3,4-dimethoxy-2-[2-[3-methoxyphenyl]ethyl]phenyl]ethyl]hexane-1,6-diaminedihydrochloride, mp 229°-231°;

(g)N-[2-Cyclohexylethyl]-N'-[2-[3,4-dimethoxy-2-[2-[3-methoxyphenyl]ethyl]phenyl]ethyl]hexane-1,6-diaminedihydrochloride, mp 227°-228°;

(h) N-[2-[3,4-Dimethoxy-2-[2-[3-methoxyphenyl]ethyl]phenyl]ethyl]-N'-[2-[4-nitrophenyl]ethyl]hexane-1,6-diaminedihydrochloride, mp 197°-198°;

(i)N-[2-[3,4-Dimethoxy-2-[2-[3-methoxyphenyl]ethyl]phenyl]ethyl]-N'-[2-[4-pyridyl]ethyl]hexane-1,6-diaminedihydrochloride, mp 192°-194°;

(j)N-[2-[3,4-Dimethoxy-2-[2-[3-methoxyphenyl]ethyl]phenyl]ethyl]-3-[2-[2-phenylethylamino]ethylthio]propanaminedihydrochloride, prisms from isopropanol, mp 186°-188°;

(k)N-[2-[3,4-Dimethoxy-2-[2-[3-methylphenyl]ethyl]phenyl]ethyl]-N'-[2-phenylethyl]hexane-1,6-diaminedihydrochloride, mp 241°-243°;

(l)N-[2-[3,4-Dimethoxy-2-[2-[2-[3-[trifluoromethyl]phenyl]ethyl]phenyl]ethyl]-N'-[2-phenylethyl]hexane-1,6-diaminedihydrochloride, mp 223°-226°;

(m)N-[2-[3,4-Dimethoxy-2-[2-[2-[3-methylphenyl]ethyl]phenyl]ethyl]-N'-[2-[4-methoxyphenyl]ethyl]hexane-1,6-diaminedihydrochloride, mp 233°-235°;

(n)N-[2-[3,4-Dimethoxy-2-[3-[3-methoxyphenyl]propyl]phenyl]ethyl]-N'-[2-phenylethyl]hexane-1,6-diaminedihydrochloride, mp 171°-172°;

(o)N-[2-[3,4-Dimethoxy-2-[3-[3-methoxyphenyl]propyl]phenyl]ethyl]-N'-[2-[4-methoxyphenyl]ethyl]hexane-1,6-diaminedihydrochloride, mp 162°-164°;

(p) N-[2-[3,4-Dimethoxy-2-[2-[3,5-dimethoxyphenyl]ethyl]phenyl]ethyl]-N'-[2-phenylethyl]hexane-1,6-diamine dihydrochloride, mp224°-226°;

(q)N-[2-[3,4-Dimethoxy-2-[2-[3-methoxyphenyl]ethyl]phenyl]ethyl]-N'-[2-[3,4-dimethoxyphenyl]ethyl]hexane-1,6-diaminedihydrochloride, mp 205°-207°;

(r)N-[2-[3,4-Dimethoxy-2-[2-[3-methoxyphenyl]ethyl]phenyl]ethyl]-N'-[2-[4-methoxyphenyl]ethyl]octane-1,8-diaminedihydrochloride, mp 227°-229°;

(s)N-[2-[3,4-Dimethoxy-2-[2-[3-methoxyphenyl]ethyl]phenyl]ethyl]-N'-[2-[3-methoxyphenyl]ethyl]hexane-1,6-diaminedihydrochloride, mp 193°-195°;

(t)N-[2-[3,4-Dimethoxy-2-[2-[3-methoxyphenyl]ethyl]phenyl]ethyl]-N'-[2-[4-methylphenyl]hexane-1,6-diaminedihydrochloride, mp 218°-220°;

(u)N-[2-[3,4-Dimethoxy-2-[2-[3-methoxyphenyl]ethyl]phenyl]ethyl]-N'-[2-[2,3-dimethoxyphenyl]ethyl]hexane-1,6-diaminedihydrochloride, mp 201.5°-202.5°;

(v)N-[2-[3,4-Dimethoxy-2-[2-[3-methoxyphenyl]ethyl]phenyl]ethyl]-N'-hexylhexane-1,6-diamine dihydrochloride, mp 194°-196°;

(w)N-[2-[3,4-Dimethoxy-2-[2-[3-methoxyphenyl]ethyl]phenyl]ethyl]-N'-[2-[3-fluoro-3,4-dimethoxyphenyl]ethyl]hexane-1,6-diaminedihydrochloride, mp 182°-184°;

(x)N-[2-[3,4-Dimethoxy-2-[2-[3-methoxyphenyl]ethyl]phenyl]ethyl]-N'-[2-[3-fluoro-4-methoxyphenyl]ethyl]hexane-1,6-diaminedihydrochloride, mp 200°-202°;

(y)N-[2-[2-[2-[3-Chlorophenyl]ethyl]-3,4-dimethoxyphenyl]ethyl]-N'-[2-phenylethyl]hexane-1,6-diaminedihydrochloride, mp 246°-247°;

(z)N-[2-[2-[2-[3-Chlorophenyl]ethyl]-3,4-dimethoxyphenyl]ethyl]-N'-[2-[4-methoxyphenyl]hexane-1,6-diaminedihydrochloride, mp 238°-240°;

(aa)N-[2-Cyclohexylethyl]-N'-[2-[3,4-dimethoxy-2-[2-[4-methoxyphenyl]ethyl]phenyl]ethyl]hexane-1,6-diaminedihydrochloride, mp 225.5°-226.5°;

(bb)N-[2-[3,4-Dimethoxy-2-[2-[4-methoxyphenyl]ethyl]phenyl]ethyl]-N'-[2-[4-methoxyphenyl]ethyl]hexane-1,6-diaminedihydrochloride, mp 198°-99°;

(cc)N-[2-[3,4-Dimethoxy-2-[4-[3-methoxyphenyl]butyl]phenyl]ethyl]-N'-[2-phenylethyl]hexane-1,6-diaminedihydrochloride, mp 215°-217°;

(dd)E-N-[2-[3,4-Dimethoxy-2-[2-[3-methoxyphenyl]ethyl]phenyl]ethyl]-N'-[2-phenylethyl]-3-hexene-1,6-diaminedihydrochloride, mp 212°-216°;

(ee)N-[4-[2-[6-[2-[3,4-Dimethoxy-2-[2-[3-methoxyphenyl]ethyl]phenyl]ethylamino]hexylamino]ethyl]phenyl]methane-sulphonamidedihydrochloride, mp 277°-279°;

(ff)N-[2-[3,4-Dimethoxy-2-[2-[3-methoxyphenyl]ethylphenyl]ethyl]-N'-[2-phenylethyl]heptane-1,7-diamine,mp 227°-229°;

(gg) N-[2-[3,4-Dimethoxy-2-[2-[3-methoxyphenyl]ethyl]phenyl]ethyl]-N'-[2-phenylethyl]nonane-1,9-diamine dihydrochloride, mp173°14 175°;

(hh)N-[2-[3,4-Dimethoxy-2-[2-[3-methoxyphenyl]ethyl]phenyl]ethyl]-N'-[2-phenylethyl]decane-1,10-diaminedihydrochloride, mp 178°-180°;

(ii)N-[2-[3,4-Dimethoxy-2-[2-[3-methoxyphenyl]ethyl]phenyl]ethyl]-N'-[2-phenylethyl]-3-methylpentane-1,5-diaminedihydrochloride, mp 241°-243°;

(jj)N-[2-[3,4-Dimethoxy-2-[2-[3-methoxyphenyl]ethyl]phenyl]ethyl]-N'-[2-phenylethyl]-3,3-dimethylpentane-1,5-diaminedihydrochloride, mp 157°-159°;

(kk)N-[2-[3,4-Dimethoxy-2-[2-[3-methoxyphenyl]ethyl]phenyl]ethyl]-N'-[2-phenylethyl]pentane-1,5-diaminedihydrochloride, mp 242°-244°;

(ll)N-[2-[5-Chloro-3,4-dimethoxy-2-[2-[3-methoxyphenyl]ethyl]phenyl]ethyl]-N'-[2-phenylethyl]hexane-1,6-diaminedihydrochloride, mp 234°-236°;

(mm)N-[2-[5-Chloro-3,4-dimethoxy-2-[2-[4-methoxyphenyl]ethyl]phenyl]ethyl]-N'-[2-phenylethyl]hexane-1,6-diaminedihydrochloride, mp 211°-213°;

(nn)N-[2-[3,4-Dimethoxy-5-[2-[3-methoxyphenyl]ethyl]phenyl]ethyl]-N'-[2-phenylethyl]hexane1,6-diamine dihydrochloride, mp 199°-201°;

(oo)N-[2-[4,5-Dimethoxy-2-[2-[3-methoxyphenyl]ethyl]phenyl]ethyl]-N'-[2-phenylethyl]hexane-1,6-diaminedihydrochloride, mp 196°-197.5°;

(pp)N-[2-[3,4-Dimethoxy-2-[2-[3-methoxyphenyl]ethyl]phenyl]ethyl]-N'-methyl-N'-[2-phenylethyl]hexane-1,6-diaminedihydrochloride, softens 138°, mp 148°-150°;

(qq)N-[2-[3,4-Dimethoxy-2-[2-[3-methoxyphenyl]ethyl]phenyl]ethyl]-N'-N'-di[2-phenylethyl]hexane-1,6-diaminedihydrochloride, mp 153.5°-155°;

(rr)N-[2-[3,4-Dimethoxy-2-[2-[3-methoxyphenyl]ethyl]phenyl]ethyl]-N'-[2-[4-methoxyphenyl]ethyl]-N'-[2-phenylethyl]hexane-1,6-diaminedihydrochloride hydrate, mp 71°-72°.

11.N-[2-[3,4-Dimethoxy-2-[2-[3-methoxyphenyl]ethyl]phenyl]ethyl]-3-[2-[2-phenylethylamino]ethanesulphonyl]propanamine

A solution of trifluoroacetic anhydride (6 ml) in dry dichloromethane(40 ml) was added dropwise to a stirred solution of Intermediate 10 j)(6.45 g) and triethylamine (4.5 ml) in dry dichloromethane (120 ml). Themixture was stirred for 16 hours then washed with 2N hydrochloric acid,saturated sodium bicarbonate solution and water, dried (MgSO₄), filteredand evaporated to give the bis-trifluoroacetyl derivative as a viscousoil (8 g).

A solution of the bis-trifluoroacetyl derivative (4 g) in drydichloromethane (100 ml) was cooled to -10° and treated with stirringwith m-chloroperoxybenzoic acid (3.0 g). The mixture was allowed to warmto room temperature and stirred for 4 hours. The solution was washedwith saturated sodium bicarbonate solution and water, dried (MgSO₄),filtered and evaporated. Purification by flash chromatography (Merck9385 silica gel) eluting with ethyl acetate/40:60 petrol (2:1) and thenethyl acetate gave the trifluoroacetyl derivative of the title compoundas a yellow oil (3.3 g).

A solution of this oil in methanol (70 ml) containing anhydrouspotassium carbonate (1.32 g) and water (10 ml) was heated to refluxtemperature in a nitrogen atmosphere for 3 hours. The methanol wasremoved under vacuum and the aqueous residues extracted with chloroform.The organic solution was dried (MgSO₄), filtered and evaporated to leavean oil which gave a white precipitate on treatment with ethereal/HCl (20ml). The filtered solid crystallised from ethanol to give thesesquihydrate of the hydrochloride of the title compound as prisms(0.8), mp 166.3°-168.5°.

12.N-[2-[4-Aminophenyl]ethyl]-N'-[2-[3,4-dimethoxy-2-[2[3-methoxyphenyl]ethyl]phenyl]ethyl]hexane-1,6-diaminetrihydrochloride hemihydrate

A solution of Intermediate 10 h) (1.4 g) in dry methanol (100 ml) washydrogenated at atmospheric pressure and room temperature over aplatinum oxide catalyst (0.23 g) for 4 hours. The catalyst was filteredoff and the solution evaporated to give the title compound as a solidwhich crystallised from ethanol (1.05 g), mp 211°-214°.

13.N-[2-[4-[Methanesulphonyl]aminophenyl]ethyl]-N'-[2-[3,4-dimethoxy-2-[2-[3-methoxyphenyl]ethyl]phenyl]ethyl]hexane-1,6-diamide

(a)N-[2-[4-Aminophenyl]ethyl]-N'-[2-[3,4-dimethoxy-2-[2-[3-methoxyphenyl]ethyl]phenyl]ethyl]hexane-1,6-diamide

A solution of Intermediate 8 d) (3.6 g) in dry methanol (150 ml) and dryethanol (100 ml) was hydrogenated over a platinum oxide catalyst atatmospheric pressure at room temperature for 4 hours. The catalyst wasfiltered and the filtrate evaporated to leave the sub-title compound asa colourless solid (3.5 g), mp 163°-165°.

(b)N-[2-[4-[Methanesulphonyl]aminophenyl]ethyl]-N'-[2-[3,4-dimethoxy-2-[2-[3-methoxyphenyl]ethyl]phenyl]ethyl]hexane-1,6-diamide

Methanesulphonylchloride (0.41 ml) was added to a stirred solution ofthe Intermediate a) (2.74 g) and triethylamine (0.74 ml) in drydimethylformamide. The solution was stirred at room temperature for 10hours.

The solution was poured onto brine and extracted with ethyl acetate. Theorganic phase was washed with 2N hydrochloric acid, brine, dried(MgSO₄), filtered and evaporated to give a red solid which crystallisedfrom isopropanol to give the title compound as a pink solid (1.72 g), mp157°-159°.

14. Preparation of3-[2-[3-Hydroxyphenyl]ethyl]-4-[2-[6-[2-phenylethoxy]hexylamino]ethyl]-1,2-benzenediol

(a)2-[2-[3-(phenylmethoxy)phenyl]ethyl]-3,4-bis(phenylmethoxy)benzeneacetonitrile.

To the 2-[2-[(3-methoxyphenyl)ethyl]-3,4-dimethoxybenzeneacetonitrile (5g) in dichloromethane (100 ml) at -78°, under nitrogen was added 1Mboron tribromide (80 ml) in dichloromethane. The reaction was thenstirred at room temperature for 4 hours. Ice/water (50 ml) was added andthe aqueous extracted with ether. The ethereal layer was dried (MgSO₄)and concentrated to give a purple oil. This oil was dissolved in drydimethylformamide (100 ml) and then potassium carbonate (22.18 g)followed by benzyl bromide (16.5 g) were added. The reaction was stoppedand stirred at room temperature for 14 hours. Ice/water was added, theaqueous layer extracted with ether, the ethereal layer washed withbrine, dried (MgSO₄) and concentrated to give a yellow oil. This waspurified by flash column chromatography on silica gel usingether:petroleum ether 40°-60°; 1:2; v/v to give 2.6 g of the sub-titlecompound as a white solid, mp 90° (softens)--95°- 97° melts.

(b) 3,4-Bis(phenylmethoxy)-2-[2-(3-(phenylmethoxy)phenyl)ethyl]phenylethylamine hydrochloride

To the nitrile (3 g) from step a) in dry tetrahydrofuran (100 ml) undernitrogen was added 1M borane in tetrahydrofuran (10 ml). The mixture washeated under reflux for 3 hours. Methanol (40 ml) was added to thecooled reaction mixture and the solution evaporated to dryness. Theresidue was dissolved in methanol (150 ml) and concentrated hydrochloricacid (15 ml) added. The mixture was heated under reflux for 1 hour andthen the solution was evaporated to dryness to yield a white solid.Recrystallisation from isopropanol gave 2 g of the sub-title compound asa white solid, mp 212°-214°.

(c)N-(2-(2-(3-(Phenylmethoxy)phenylethyl)-3,4-bis(phenylmethoxy)phenyl)ethyl)-2,2,2-trifluoroacetamide

To the amine hydrochloride (2 g) from step (b) in dichloromethane (100ml) was added triethylamine (0.66 g) followed by trifluoroaceticanhydride (0.68 g) and N,N-dimethylaminopyridine (10 mg). The reactionmixture was stirred at room temperature for 14 hours. Chloroform wasadded to the reaction, the organic layer was separated and then washedwith 2N hydrochloric acid, saturated sodium bicarbonate solution, brine,dried (MgSO₄) and evaporated to give a white solid. Recrystallisationfrom ether/petroleum ether 40°-60° gave the sub-title compound (1.6 g aswhite prisms, mp 142°-144°.

(d) N-[6-(2-Phenylethoxy)hexyl]-N-(2-(2-(3-(phenylmethoxy)phenylethyl-3,4-bis(phenylmethoxy)phenylethyl-2,2,2-trifluoroacetamide

The trifluoroacetamide (1.6 g) from step c) in dry dimethylformamide (20ml) was added to a stirred suspension of NaH (80 mg, oil-free) in drydimethylformamide (15 ml) under nitrogen. The mixture was stirred at 70°for 1.5 hours. 2-(6-bromohexyloxy)-1-phenylethane (0.8 g) in drydimethylformamide (10 ml) was then added dropwise and the reactionstirred at room temperature for 14 hours. The solvent was then removed,2N hydrochloric acid (30 ml) was added and the aqueous extracted withethyl acetate. The ethyl acetate layer was washed with brine, dried(MgSO₄) and concentrated to give an oil. The oil was purified by columnchromatography (silica, petroleum ether 40°-60°:ether, 3:2, v/v) to givethe sub-title compound as a colourless oil (0.6 g), m/e 855 (MH⁺).

(e) N-[6-(2-Phenylethoxy)hexyl]-N-(2-(2-(3-(phenylmethoxy)phenylethyl)-3,4-bis(phenylmethoxy)phenylethylamine hydrochloride

The amide from step (d) (0.6 g) in methanol (25 ml) and sodium hydroxide(60 mg) in water (10 ml) was refluxed for 3 hours, Methanol was removedin vacuo and the aqueous extracted with ethyl acetate to give an oil.This oil was purified by column chromatography (silica; CHCl₃ MCOH; 9:1;v/v) to give the product as an oil. The oil was taken up in ether,ethereal hydrogen chloride was added to give a white solid which wasfiltered off and dried to give the hydrochloride salt of the titlecompound (100 mg), mp 151°-153°.

15. Alternative route for the preparation of benzene methanols, viaWittig reaction Phosphonium salt formation

(a) Ethyl 3,4-dimethoxy-2-methyl benzoate

A solution of 3,4-dimethoxy-2-methylbenzoic acid (5.9 g) in ethanol (200ml) containing concentrated hydrochloric acid (10 ml) was heated atreflux temperature for 16 hours. The cool solution was evaporated downto an oil then dissolved in ether. The organic solution was washed with1N sodium hydroxide solution (100 ml), brine (100 ml), dried (MgSO₄),filtered and evaporated to leave a solid.

The solid was purified by flash chromatography eluting with 60/80 petrolether/ethyl acetate (10:1) to give the sub-title ester as colourlessneedles (6.58 g), mp 46°-49°.

(b) Ethyl 2-bromomethyl-3,4-dimethoxybenzoate

A solution of the ester (stage a) (67.2 g), N-bromosuccinimide (57 g)and azobisisobutyronitrile (catalytic) in carbontetrachloride (700 ml)was heated under reflux under irradiation (60 w bulb) for 21/2 hours.The cooled reaction was washed with water.

The organic solution was dried (MgSO₄), filtered and evaporated to leavea solid. The solid was purified by flash chromatography (Merck 9385silica gel) eluting with dichloromethane /60/80 petrol ether (1:1).Evaporation of the required fractions gave a yellow solid (84.1 g), msm/e 302/304.

Similarly prepared was:

(b.1) 2-[2-Bromomethyl3,4-dimethoxyphenyl]-4,5-dihydro-4,4-dimethyloxazole, ms m/e 327/329.

(c) 6-Ethoxycarbonyl-2,3-dimethoxyphenyl]methyltriphenyl phosphoniumbromide

A solution of the product of step (b) (83.9 g) and triphenylphosphine(72.55 g) in toluene (500 ml) was heated under reflux in a nitrogenatmosphere for 24 hours. The precipitate from the cooled solution wasfiltered, slurried with ether and stirred for 2 hours. The solid wasfiltered and dried (129 g), mp 198°-200°.

Similarly prepared was:

(c.1)[6-[4,5-Dihydro-4,4-dimethyloxazole-2-yl]-2,3-dimethoxyphenyl]methyltriphenylphosphoniumbromide, ms m/e 510 (cation)

Variation A - oxazole route

Wittig reaction

(Aa)E-2-[3,4-Dimethoxy-2-[2-[3-nitrophenyl]ethenyl]phenyl]4,5-dihydro-4,4-dimethyloxazole

A solution of the phosphonium bromide from step c.1) (69 g) in drydimethylformamide (300 ml) was added dropwise to a suspension of 80%sodium hydride (3.51 g) stirred in dry dimethylformamide (100 ml) at 0°under a nitrogen atmosphere. The mixture was stirred for 30 minutes at60° and a solution of 3-nitrobenzaldehyde (17.7 g) in drydimethylformamide (100 ml) was then added.

The mixture was stirred at 20° for 1 hour then quenched with ice/water.

The solid mass was extracted into ethyl acetate and separated. Theorganic solution was washed with water, dried (MgSO₄), filtered andevaporated to give a yellow oil which was purified by flashchromatography (Merck 9385 silica gel) eluting withdichloromethane/ethyl acetate (95:5). Evaporation of the relevantfractions gave the sub-title compound as pure E isomer (35 g), mp78°-80°.

Reduction of nitro group

(Ab)E-3-[2-[6-[4,5-Dihydro-4,4-dimethyloxazole-2-yl]-2,3-dimethoxyphenyl]ethenyl]benzeneamine

A solution of the nitro intermediate Aa) (32 g) in ethanol (250 ml) washydrogenated over a platinum oxide catalyst (0.3 g) at 2 atmospheres for2 hours. The catalyst was removed by filtration and the filtrateevaporated to leave a colourless solid (26.5 g), ms m/e 352.

Sulphonamide formation and cleavage of oxazole

(Ac)E-3,4-Dimethoxy-2-[2,[3-[methanesulphonyl]aminophenyl]ethenyl]benzoicacid

Methanesulphonylchloride (12.4 ml) was added dropwise to a stirredsolution of the benzenamine Ab) (26.5 g) and triethylamine (24 ml) indry dichloromethane (200 ml). The solution was stirred at 20° for 1hour. The solution was washed with water, dried (MgSO₄), filtered andevaporated to leave 29 g of the dimethanesulphonamide intermediate.

A solution of this intermediate in methyliodide (50 ml) anddichloromethane (200 ml) was heated at reflux temperature for 2 days.The solution was evaporated and the residue triturated with ether togive 41 g of the quaternary salt as a yellow solid, mp 193°.

A solution of the quaternary salt in methanol (800 ml) and 10% sodiumhydroxide solution (160 ml) was heated to reflux temperature for 3hours. The solution was evaporated and acidified with 2N hydrochloricacid. The solid precipitate was filtered, washed with water and dried.The solid crystallised from ethanol to give 20.5 g of the acid as acolorless solid, mp 221°-223°.

Reduction of double bond

(Ad) 3,4-Dimethoxy-2-[2-[3-[methanesulphonyl]aminophenyl]ethyl]benzoicacid.

A solution of the acid (Ac) (8.15 g) in 1M sodium hydroxide solution(200 ml) was hydrogenated over a 10% palladium on charcoal catalyst (2g) at 3 atmospheres and 45° for 18 hours. The catalyst was removed byfiltration and the cooled solution acidified with 2N hydrochloric acid.The solid was dissolved in ethyl acetate and separated. The organicsolution was washed with water, dried (MgSO₄), filtered and evaporatedto leave a solid. Crystallisation from ethylacetate/petrol gave 6.26 gof the acid as a colourless powder, mp 187.5°-188.5°.

Variation B - benzoate ester route

Wittig reaction

(Ba) E/Z-Ethyl-2-[2-[3,5-Dimethoxyphenyl]ethenyl]3,4-dimethoxy benzoate

A 1.6M solution of butyl lithium in hexane (55 ml) was added dropwise toa stirred suspension of the phosphonium salt (45.2 g) from step 15 c) indry tetrahydrofuran (200 ml) under a nitrogen atmosphere at 0°. Themixture was stirred at 0° for 1 hour and a solution of3,5-dimethoxybenzaldehyde added. The resulting mixture was stirred at20° for 16 hours.

The mixture was quenched with brine (50 ml) and evaporated to dryness.The solid was dissolved in ethyl acetate washed with brine, dried(MgSO₄), filtered and evaporated to give a dark oil. The oil waspurified by flash chromatography (Merck 9385 silica gel) eluting withdichloromethane/petrol 60/80 (1:1) to give 24 g of the intermediateester as a colourless oil, ms m/e 372.

Similarly prepared were:

(Ba.1) E-Ethyl3,4-Dimethoxy-2-[2-[3,4,5-trimethoxyphenyl]ethenyl]benzoate, mp103°-104°;

(Ba.2) E/Z-Ethyl 3,4-Dimethoxy-2-[2-[3-nitrophenyl]ethenyl]benzoate, mp80°-82°.

(Ba.3) Ethyl 3,4-dimethoxy-5-[2-[3-methoxyphenyl]ethenyl]benzoate, m/e342.

Reduction of double bond

(Bb) Ethyl-2-[2-[3,5-Dimethoxyphenyl]ethyl]3,4-dimethoxy benzoate

A solution of the intermediate ethenyl ester Ba) (24 g) in ethanol (150ml) was hydrogenated over a 10% palladium on charcoal catalyst (1 g) atatmospheric pressure for 24 hours. The catalyst was removed byfiltration and the filtrate evaporated to leave a yellow oil. The oilwas purified by flash chromatography (Merck 9385 silica gel) elutingwith 60/80 petrol ether/10% ethyl acetate to give 20 g of theintermediate ester as a colourless oil, ms m/e 374.

Similarly prepared were:

(Bb.1) Ethyl 3,4-dimethoxy-2-[2-[3,4,5-trimethoxyphenyl]ethyl]benzoate,ms m/e 440;

(Bb.2)3,4-Dimethoxy-2-[2-[3,4,5-trimethoxyphenyl]ethyl]benzeneacetonitrile, mp119.5°-120.5°;

(Bb.3) Ethyl 3,4-dimethoxy-5-[2-[3-methoxyphenyl]ethyl]benzoate, ms m/e344.

Selective reduction of the double bond of the intermediate Ba.2

(Bc) Ethyl-3,4-dimethoxy-2-[2-[3-nitrophenyl]ethyl]benzoate

A solution of the ethenyl ester (Ba.2) (5 g) in benzene (100 ml) washydrogenated over Wilkinson's catalyst at 65 atmospheres for 48 hours.

The mixture was evaporated to dryness and purified by flashchromatography (Merck 9385 silica gel) eluting with ethylacetate/60/80petrol ether (1:3) to give the ester as a colourless powder (4.83 g).

16. Alternative routes to benzeneethanamines

(a) 2-[2-[3,5-Dimethoxyphenyl]ethyl]3,4-dimethoxy benzaldehyde

A solution of the intermediate alcohol 3 (Ba) (13.3 g) in drydichloromethane containing activated manganese dioxide (60 g) wasvigorously stirred at 20° for 2 hours. The suspension was filtered andthe filtrate evaporated to give 13.2 g of the aldehyde as a white solid,mp 88°-89°.

Similarly prepared was:

2-[2-[3,4-dimethoxyphenyl]ethyl]-3,4-dimethoxy benzaldehyde, ms m/e 330.

(b)[2-[3,5-Dimethoxyphenyl]ethyl]-1,2-dimethoxy-4-[E-2-nitroethenyl]benzene

A solution of the aldehyde 16 (a) (10.8 g) in n-butylamine (15 ml) washeated at 110° for 2 hours. The solution was evaporated, dissolved inether, dried (MgSO₄), filtered and evaporated to give 12.1 g of thebutylimine as a solid, mp 67°-68°.

A solution of the imine (12.lg) and nitromethane (4 ml) in glacialacetic acid was heated at 100° for 4 hours. The solution was evaporatedand the residue dissolved in ethyl acetate. The organic solution waswashed with brine, dried (MgSO₄), filtered and evaporated.Crystallisation from isopropanol gave 10.8 g of the nitrostyrene asyellow prisms, mp 110°-112°.

Similarly prepared was:

(b.1)3-[2-[3,4-Dimethoxyphenyl]ethyl]-1,2-dimethoxy-4-[E-2-nitroethenyl]benzene,mp 95°-96°.

Reduction - Method A:

(c) 2-[2-[3,5-Dimethoxyphenyl]ethyl]-3,4-dimethoxybenzeneethanamine

A 1M solution of lithium aluminium hydride in tetrahydrofuran (60 ml)was added dropwise to a stirred solution of the nitro compound (b) (3.7g) in dry tetrahydrofuran under a nitrogen atmosphere. The solution wasstirred at 20° for 24 hours. The cooled solution was treated with 2Nsodium hydroxide solution until precipitation was complete. The solidmass was extracted with warm ethyl acetate. The organic solution wasdried (MgSO₄), filtered and evaporated to leave a yellow oil.Trituration with ethereal hydrogen chloride gave a pink solid (2.6 g).

This was purified by reverse phase semi preparitive HPLC (Dynamax 60ASiO₂ column) eluting with water with 0.1% trifluoroacetic acid/methanol(50:50). Evaporation of the relevant fractions gave an oil which wasbasified with 10% sodium hydroxide solution and extracted into ethylacetate. The organic solution was dried (MgSO₄), filtered and evaporatedto leave a colourless oil. Trituration with ethereal hydrogen chloridegave a solid which crystallised from isopropanol to give 1.35 g of thesub-title compound as the hydrochloride salt, mp 179°-180°.

Reduction - Method B:

(d) 2-[2-[3,4-Dimethoxyphenyl]ethyl]-3,4-dimethoxybenzeneethanamine

Sodium borohydride (2.8 g) was added portionwise over 10 minutes to astirred suspension of the nitrostyrene (b.1) (5.6 g) and silica gel(Fluka 60) (28 g) in chloroform (200 ml) and isopropanol (50 ml). Thesuspension was stirred at 20° for 16 hours. The silica gel was removedby filtration and the solvent evaporated to dryness to give theintermediate nitroethane as a pale yellow oil.

A solution of the oil in ethanol (100 ml) was hydrogenated over aplatinum oxide catalyst (20 mg) at 3 atmospheres and 45° for 7 days.

The catalyst was removed by filtration and the filtrate evaporated.Trituration with ethereal hydrogen chloride gave a grey solid. This waspurified by reverse phase HPLC (Dynamax 60A SiO₂ column) eluting withwater with 0.1% trifluoroacetic acid/methanol (55:45). Evaporation ofthe relevant fractions gave an oil which was basified with 10% sodiumhydroxide solution and extracted into ethyl acetate. The organicsolution was dried (MgSO₄), filtered and evaporated to leave acolourless oil. Trituration with ethereal hydrogen chloride gave a solidwhich crystallised from isopropanol to give 1.3 g of the sub-titlecompound as the hydrochloride salt, mp 152°-153°.

17. Preparation of3,4-Dimethoxy-2-[2-[3-methoxyphenyl]ethyl]-N,N-Di-propylbenzeneethanaminehydrochloride

A mixture of 3,4-Dimethoxy-2-[2-[3-methoxyphenyl]ethyl]benzeneethanaminehydrochloride (3.5 g), potassium carbonate (6.9 g), n-propyliodide (3.9ml) in acetonitrile (120 ml) was heated at reflux temperature for 4hours.

The solution was filtered whilst hot and evaporated to dryness. Theresidue was dissolved in ethyl acetate and washed with water. Theorganic solution was dried (MgSO₄), filtered and evaporated to give anoil which was purified by flash chromatography (Merck 9385 silica gel)eluting with dichloromethane/5% methanol. The relevant fractions wereevaporated to give a colourless oil (2.0 g). The oil in ether (20 ml)was treated with ethereal hydrogen chloride. The precipitate wasfiltered and crystallised from isopropanol (1.9 g), mp 159°-160°.

18. Preparation of3,4-Dimethoxy-2-[2-[3-methoxyphenyl]ethyl]-N-[1-methylethyl]benzeneethanaminehydrochloride

(a) 3,4-Dimethoxy-2-[2-[3-methoxyphenyl]ethyl]benzeneacetic acid

A solution of3,4-Dimethoxy-2-[2-[3-methoxyphenyl]ethyl]benzeneacetonitrile (4.9 g)and potassium hydroxide (4.41 g) in ethanol (150 ml) and water (50 ml)was heated under reflux for 18 hours. The mixture was evaporated todryness and the residue dissolved in water and extracted with ethylacetate. The organic solution was washed with brine, dried (MgSO₄),filtered and evaporated to leave the sub-title compound as an oil whichsolidified on trituration with petrol ether (1.72 g), mp 77°-79°.

(b)3,4-Dimethoxy-2-[2-[3-methoxyphenyl]ethyl]-N-[1-methylethyl]benzeneacetamide

A solution of the acid from step (a) (2.18 g) and thionyl chloride (0.96ml) in dry dichloromethane (20 ml) was heated at reflux temperature for5 hours. The solution was evaporated to dryness. A solution of the acidchloride in dry dichloromethane (20 ml) was added dropwise to anice-cold solution of isopropylamine (1.12 ml) in dry dichloromethane.The solution was stirred at 20° for 16 hours. The reaction mixture waswashed with 2N hydrochloric acid, sodium bicarbonate solution and brine,dried (MgSO₄), filtered and evaporated to leave a solid whichcrystallised from isopropanol to give the sub-title compound as prisms(1.98 g), mp 138.5°-140°.

(c)3,4-Dimethoxy-2-[2-[3-methoxyphenyl]ethyl]-N-[1-methylethyl]benzeneethanaminehydrochloride

1M Borane THF complex (25 ml) was added dropwise to a stirred solutionof the amide of step (b) (1.85 g) in dry tetrahydrofuran (50 ml) under anitrogen atmosphere. The solution was heated at reflux temperature for16 hours. The cooled solution was quenched with methanol (50 ml) andevaporated to dryness. The residue was dissolved in methanol (50 ml)containing concentrated hydrochloric acid (5 ml) and the solution heatedunder reflux for 3 hours. Evaporation gave a solid which crystallisedfrom isopropanol to give the title product as prisms (1.77 g), mp185°-186°.

B. EXAMPLES Example 13-[2-[3-Hydroxyphenyl]ethyl]-4-[2-[6-[2phenylethylamino]hexylamino]ethyl]-1,2-benzenediol

A solution of the diamine Intermediate 10 (a) (1.4 g) in 48% aqueoushydrobromic acid (20 ml) containing hypophosphorous acid (0.1 ml) washeated at reflux temperature for 3 hours under an atmosphere ofnitrogen. The solution was evaporated to dryness and the residue treatedwith ethyl acetate. The dihydrobromide salt of the title compound (1.3g) was filtered off as a beige solid and dried at 80° under vacuum, mp167°-170°.

Example 23-[2-[3-Hydroxyphenyl]ethyl]-4-[2-[4-[2phenylethylamino]butylamino]ethyl]-1,2-benzenediol

A solution of Intermediate 10 (b) (1.1 g) in concentrated hydrochloricacid (100 ml) was heated under reflux under a nitrogen atmosphere for 5days. The solution was evaporated to dryness and the residuecrystallised from isopropanol/ether as the dihydrochloride hydrate ofthe title compound (0.8 g), mp presoftens 132-134, mp 170°.

Example 33-[2-[3-Hydroxyphenyl]ethyl]-4-[2-[8-[2phenylethylamino]octylamino]ethyl]-1,2-benzenediol

A solution of 1M boron tribromide in dichloromethane (60 ml) was addeddropwise to a cooled (-78°) suspension of Intermediate 10 c) (0.617 g)in dry dichloromethane (40 ml). The mixture was stirred at roomtemperature under a N₂ atmosphere for 4 hours, then methanol (20 ml)added and the mixture evaporated to leave a solid which recrystallisedfrom ethanol/ether to give prisms of the dihydrobromide hydrate titlecompound (0.58 g), mp 175°-177°.

Example 4

The following compound was prepared from the corresponding intermediate,by the method of Example 1:

(4.1)4-[2-[6-[2-Cyclohexylethylamino]hexylamino]ethyl]-3-[2-[3-hydroxyphenyl]ethyl]-1,2-benzenediol,as a dihydrobromide salt, mp 172.5°-174.5°;

(4.2)3-[2-[3-Hydroxyphenyl]ethyl]-4-[2-[6-[2-[4-methyl-phenyl]ethylamino]hexylamino]ethyl]-1,2-benzenediol,as a dihydrobromide, mp 170°-172° decomposes;

(4.3)3-[2-[3-Hydroxyphenyl]ethyl]-4-[2-[6-[2-[3-hydroxy-phenyl]ethylamino]hexylamino]ethyl]-1,2-benzenediol,as a dihydrobromide, mp 158°-160°;

(4.4)4-[2-[6-[6-Hexylamino]hexylamino]ethyl]-3-[2-[3-hydroxyphenyl]ethyl]-1,2-benzenediol,as a dihydrobromide, mp 151°-153°;

(4.5) 4-[2-Amino ethyl]-3-[2-[3-hydroxyphenyl]ethyl]-1,2-benzenediol, asa dihydrobromide, mp 154°-156°;

(4.6) 4-[2-Amino ethyl]-3-[2-[4-hydroxyphenyl]ethyl]-1,2-benzenediol, asthe hydrobromide salt, mp 214°-216°;

(4.7) 4-[2-Aminoethyl]-3-[2-phenylethyl]-1,2-benzenediol, as thehydrobromide salt, mp 176°-177°;

(4.8)4-[2-Aminoethyl]-6-chloro-2-[2-[3-hydroxyphenyl]ethyl]-1,2-benzenediol,as the hydrobromide salt, mp 141°-143°;

(4.9)3-[2-[3-Hydroxyphenyl]ethyl]-4-[2-N,N-Di-n-propylaminoethyl]-1,2-benzenediol,as the hydrobromide salt, mp 143°-144°;

(4.10) 3-[2-[3-Hydroxyphenyl]ethyl]-4-[2-N-1methylethyl]aminoethyl]-1,2-benzenediol, as the hydrobromide salt, mp217.5°-219°;

(4.11) 4-[2-Aminoethyl]-5-[2-[3-hydroxyphenyl]ethyl]-1,2-benzenediol, asthe hydrobromide salt, mp 182 (decomposes);

(4.12) 5-[2-Aminoethyl]-3-[2-[3-hydroxyphenyl]ethyl]-1,2-benzenediol, asthe hydrobromide salt, mp 146°-148°;

(4.13)3-[2-[3-Hydroxyphenyl]ethyl]-4-[2-[7-[2-phenylethylamino]heptylamino]ethyl]-1,2-benzenediol,as a dihydrobromide, prisms, mp 187°-189°;

(4.14)3-[2-[3-Hydroxyphenyl]ethyl]-4-[2-[9-[2-phenylethylamino]nonylamino]ethyl]-1,2-benzenediol,as a dihydrobromide, mp 167°-168°;

(4.15)3-[2-[3-Hydroxyphenyl]ethyl]-4-[2-[10-[2-phenylethylamino]decylamino]ethyl]-1,2-benzenediol,as a dihydrobromide, mp 123°-125°;

(4.16)3-[2-[3-Hydroxyphenyl]ethyl]-4-[2-[5-[2-phenylethylamino]-3-methylpentylamino]ethyl]-1,2-benzenediol,as a dihydrobromide, mp 171°-173°;

(4.17)3-[2-[3-Hydroxyphenyl]ethyl]-4-[2-[5-[2-phenylethylamino]-3,3-dimethylpentylamino]ethyl]-1,2-benzenediol,as a dihydrobromide, mp 128°-130°;

(4.18)3-[2-[3-Hydroxyphenyl]ethyl]-4-[2-[5-[2-phenylethylamino]pentylamino]ethyl]-1,2-benzenediol,as a dihydrobromide, mp 171°-172°;

(4.19)3-[2-[3-Hydroxyphenyl]ethyl]-4-[2-[6-[N-methyl-N-2-phenylethylamino]hexylamino]ethyl]-1,2-benzenediol,as a dihydrobromide hemihydrate, mp 120°-122°;

(4.20)3-[2-[3-Hydroxyphenyl]ethyl]-4-[2-[6-[2-[N,N'-di-[2-phenylethyl]amino]hexylamino]ethyl]-1,2-benzenediol,as a dihydrobromide hemihydrate, mp 143°-145°;

(4.21)3-[2-[3-Hydroxyphenyl]ethyl]-4-[2-[6-[[2-[4-hydroxyphenyl]ethyl]-[2-phenylethyl]amino]hexylamino]ethyl]-1,2-benzenediol,as a dihydrobromide sesquihydrate, softens 85°-87°, mp 120°-122°.

Example 5

The following compounds were prepared from the correspondingintermediate, by the method of Example 2:

(5.1)4-[2-[6-[2-[4-Chlorophenyl]ethylamino]hexylamino]ethyl]-3-[2-[3-hydroxyphenyl]ethyl]-1,2-benzenediol,as a dihydrochloride, hydrate, as prisms , mp softens at 123°, melts at184°-187°;

(5.2) 4-[2-[6-[2,3-Dihydro-1H-indene-2-ylamino]hexylamino]ethyl]-3-[2-[3-hydroxyphenyl]ethyl]-1,2-benzenediol, asdihydrochloride hydrate, mp pre-softens 108°, melts at 127°-132°;

(5.3)3-[2-[3-Hydroxyphenyl]ethyl]-4-[2-[6-[2-[4-pyridyl]ethylamino]hexylamino]ethyl]-1,2-benzenediol,as a trihydrochloride, hydrate, mp softens 137°, decomposes 180°-189°;

(5.4)3-[2-[3-Hydroxyphenyl]ethyl]-4-[2-[6-[2-phenylethylamino]hexylamino]ethyl]-1,2-benzenediol,as a dihydrochloride 206°-208°;

Low melting dihydrochloride also isolated from ethanol, mp 141°-144°.

Example 6

The following compounds were prepared from the correspondingIntermediates 10, 11, 12, 13 or 14 by the method of Example 3:

(6.1)3-[2-[3-Hydroxyphenyl]ethyl]-4-[2-[6-[2-[4-hydroxyphenyl]ethylamino]hexylamino]ethyl-1,2-benzenediol,as a dihydrobromide hydrate, mp softens at 85°. melts at 135°-140°;

(6.2)3-[2-[3-Hydroxyphenyl]ethyl]-4-[2-[3-[2-[2-phenylethylamino]ethylthio]propylamino]ethyl]-1,2-benzenediol,as a dihydrobromide, colourless prisms, mp 122°-124°;

(6.3)3-[2-[3-Hydroxyphenyl]ethyl]-4-[2-[3-[2-[2-phenylethylamino]ethanesulphonyl]propanylamino]ethyl]-1,2-benzenediol,as a dihydrobromide hydrate, mp softens 96°-98°, mp 195°-198°;

(6.4)3-[2-[3-Hydroxyphenyl]ethyl]-4-[2-[6-[2-[4-nitrophenyl]ethylamino]hexylamino]ethyl]-1,2-benzenediol,as a dihydrobromide hydrate, mp 85°-130° decomposes;

(6.5)4-[2-[6-[2-[4-Aminophenyl]ethylamino]hexylamino]ethyl]-3-[2-[3-hydroxyphenyl]ethyl]-1,2-benzenediol,as a trihydrobromide, mp 218°-220°;

(6.6)4-[2-[6-[2-[3,4-Dihydroxy-2-[2-[3-hydroxyphenyl]ethyl]phenyl]ethylamino]hexylamino]ethyl]-3-fluoro-1,2-benzenediol,as a dihydrobromide hydrate, mp 90°-92° dec;

(6.7)4-[2-[6-[2-[3-Fluoro-4-hydroxyphenyl]ethylamino]hexylamino]ethyl]-3-[2-[3-hydroxyphenyl]ethyl]-1,2-benzenediol,as a dihydrobromide hydrate, mp 88°-90° dec;

(6.8)3-[2-[3-Methylphenyl]ethyl]-4-[2-[6-[2-phenylethylamino]hexylamino]ethyl]-1,2-benzenediol,as a dihydrobromide from isopropanol, mp 169°-171°;

(6.9)4-[2-[6-[2-[4-Hydroxyphenyl]ethylamino]hexylamino]ethyl]-3-[2-[3-methylphenyl]ethyl]-1,2-benzenediol,as a dihydrobromide from isopropanol, mp 196°-198°;

(6.10)3-[2-[3-Hydroxyphenyl]ethyl]-4-[2-[8-[2-[4-hydroxyphenyl]ethylamino]octylamino]ethyl]-1,2-benzenediol,as a dihydrobromide, mp 217°-219°;

(6.11)4-[2-[6-[2-Phenylethylamino]hexylamino]ethyl]-3-[2-[3-[trifluoromethyl]phenyl]ethyl]-1,2-benzenediol,as a dihydrobromide from ethanol/ether, mp softens 103°-105° melts145°-146° dec;

(6.12)3-[2-[3,5-Dihydroxyphenyl]ethyl]-4-[2-[6-[2-phenylethylamino]hexylamino]ethyl]-1,2-benzenediol,as a dihydrobromide hydrate, mp softens 68°-70° melts 112°-115°;

(6.13)4-[2-[6-[2-[3,4-Dihydroxyphenyl]ethylamino]hexylamino]ethyl]-3-[2-[3-hydroxyphenyl]ethyl]-1,2-benzenediol,as a dihydrobromide hydrate, mp 167°-169°;

(6.14)3-[3-[3-Hydroxyphenyl]propyl]-4-[2-[6-[2-phenylethylamino]hexylamino]ethyl]-1,2-benzenediol,as a dihydrobromide, hydrate melts 77°-79° decomposes;

(6.15)3-[3-[3-Hydroxyphenyl]propyl]-4-[2-[6-[2-[4-hydroxyphenyl]ethylamino]hexylamino]ethyl]-1,2-benzenediol,as a dihydrobromide hydrate, mp 92°-94° decomposes;

(6.16)4-[2-[6-[2-[2,3-Dihydroxyphenyl]ethylamino]hexylamino]ethyl]-3-[2-[3-hydroxyphenyl]ethyl]-1,2-benzenediol,as a dihydrobromide

(6.17)3-[2-[3-Chlorophenyl]ethyl]-4-[2-[6-[2-phenylethylamino]hexylamino]ethyl]-1,2-benzenediol,as a dihydrobromide from ethanol, mp 188°-190°;

(6.18)3-[2-[3-Chlorophenyl]ethyl]-4-[2-[6-[2-[4-hydroxyphenyl]ethylamino]hexylamino]ethyl]-1,2-benzenediol,as a dihydrobromide, mp 206°-208°;

(6.19)4-[2-[6-[2-Cyclohexylethylamino]hexylamino]ethyl]-3-[2-[4-hydroxyphenyl]ethyl]-1,2-benzenediol,as a dihydrobromide, mp 194°-195°;

(6.20)3-[2-[4-Hydroxyphenyl]ethyl]-4-[2-[6-[2-[4-hydroxy-phenyl]ethylamino]hexylamino]ethyl]-1,2-benzenediol,as a dihydrobromide, mp 98°-101°;

(6.21)3-[4-[3-Hydroxyphenyl]butyl]-4-[2-[6-[2-phenylethylamino]hexylamino]ethyl]-1,2-benzenediol,as a dihydrobromide, hydrate mp 72°-74° decomposes;

(6.22)3-[2-[3-[Hydroxyphenyl]ethyl]-4-[2-[6-[2-[4-pyridyl]ethylamino]hexylamino]ethyl]-1,2-benzenediol,as a trihydrobromide hydrate softens 180°, melts 189°-190°;

(6.23)E-3-[2-[3-Hydroxyphenyl]ethyl]-4-[2-[6-[2-phenylethylamino]-3-hexenylamino]ethyl]-1,2-benzenediol,as a dihydrobromide. m/e FAB 475 (+1);

(6.24)N-[4-[2-[6-[2-[3,4-Dihydroxy-2-[2-[3-hydroxyphenyl]ethyl]phenyl]ethylamino]hexylamino]ethyl]phenyl]methanesulphonamidedihydrobromide, mp softens 76°-78°, melts 146°-149°;

(6.25)4-[2-Aminoethyl]-3-[2-[3,5-dihydroxyphenyl]ethyl]-1,2-benzenediol, mp222°-224°;

(6.26)5-[2-[6-[2-Aminoethyl]2,3-dihydroxyphenyl]ethyl]1,2,3-benzenetriol, as ahydrobromide, mp 225°-227°;

(6.27) 4-[2-Aminoethyl]-3-[2-[3,4-dihydroxyphenyl]ethyl]1,2-benzenediol,as a hydrobromide, mp 118°-120° (decomposes);

(6.28) 4-[2-Aminoethyl]-3-[2-[3-nitrophenyl]ethyl]1,2-benzenediol, as ahydrobromide, mp 217°-218°;

(6.29)N-[3-[2-[6-[2-Aminoethyl]-2,3-dihydroxy]phenyl]ethyl]phenyl]methanesulphonamide,as a hydrobromide, mp 189°-191°;

(6.30)6-Chloro-3-[2-[3-Hydroxyphenyl]ethyl]-4-[2-[6-[2-phenylethylamino]hexylamino]ethyl]1,2-benzenediol,as a dihydrobromide, mp 157°-159°;

(6.31)6-Chloro-3-[2-[4-Hydroxyphenyl]ethyl]-4-[2-[6-[2-phenylethylamino]hexylamino]ethyl]1,2-benzenediol,as a dihydrobromide, mp 161°-164°;

(6.32)3-[2-[3-Hydroxyphenyl]ethyl]-5-[2-[6-[2-phenylethylamino]hexylamino]ethyl]1,2-benzenediol,as a dihydrobromide hemihydrate, mp 60°-70°;

(6.33)5-[2-[3-Hydroxyphenyl]ethyl]-4-[2-[6-[2-phenylethylamino]hexylamino]ethyl]1,2-benzenediol,as a dihydrobromide hemihydrate, mp 120°-150° (decomposes);

(6.34) 4-[2-Aminoethyl]-6-chloro-3-[2-[2-[4-hydroxyphenyl]ethyl]-1,2-benzenediol, as the hydrobromide salt, softens 128°-130°, mp162°-164°.

Example 7 4-[2-[6-(2-Phenylethoxy)]hexylamino]ethyl3-[2-[3hydroxyphenyl]ethyl]-1,2-benzenediol

The Intermediate from A 14 (e) (100 mg) was dissolved in dry ethanol (50ml) and then hydrogenated over 10% palladium on carbon (25 mg). Thecatalyst was removed by filtration and the filtrate concentrated invacuo to give the hydrochloride salt of the title compound as a glassysolid (60 mg), m/e M⁺ 478 (+1).

Example 8 3-[2-[3-Hydroxyphenyl]ethyl-4-[2-[6-[2-hydroxy-2-phenylethylamino]hexylamino]ethyl]-1,2-benzenediol

(a)6-[2-[3,4-Di(phenylmethoxy)-2-[2-[3-(phenylmethoxy]phenyl]ethyl]phenyl]ethylamino]-6-oxohexanoicacid

A solution of monomethyladipate (0.74 ml) and triethylamine (0.69 ml) indry dichloromethane (50 ml) was stirred at 0° during the dropwiseaddition of a solution of ethyl chloroformate (0.48 ml) in drydichloromethane (20 ml). The mixture was stirred under an atmosphere ofnitrogen at 0° for 30 minutes and a solution of3,4-Di(phenylmethoxy)-2-[2-[3-(phenylmethoxy]phenyl]ethyl]benzeneethanamine(2.70 g) in dry dichloromethane (50 ml) was then added. The mixture wasstirred at 20° for 18 hours.

The reaction mixture was washed with 2N hydrochloric acid, saturatedsodium bicarbonate solution, water, dried (MgSO₄), filtered andevaporated. Crystallisation from petrol ether 60/80 gave theintermediate ester (2.87 g) as a colourless solid, mp 120°-121°.

A solution of the ester (2.87 g) in methanol (30 ml) and 10% potassiumhydroxide solution (5 ml) was heated at reflux temperature for 3 hours.The solution was evaporated and the residue acidified with 2Nhydrochloric acid. The solid mass was dissolved in ethyl acetate (200ml), washed with water, dried (MgSO₄), filtered and evaporated to give asolid. Crystallisation from ethyl acetate/60:80 petrol ether gave thesub-title acid as colourless prisms, mp 160°-162°.

(b)N-[2-Hydroxy-2-phenyl]ethyl-N'-[2-[3,4-Di(phenylmethoxy)-2-[2-[3-(phenylmethoxy)phenyl]ethyl]phenyl]hexane-1,6-diamide

A solution of the product from step (a) (2.41 g) andN,N-carbonyldiimidazole (0.583 g) in dry dichloromethane (50 ml) wasstirred at 20° under nitrogen for 2 hours and a solution of2-amino-1-phenylethanol (0.54 g) in dry dichloromethane (20 ml) was thenadded. The mixture was stirred at 20° for 16 hours. Chloroform (50 ml)was added and the mixture washed with 2N hydrochloric acid, saturatedsodium bicarbonate, water, dried (MgSO₄), filtered and evaporated togive a solid. Crystallisation from chloroform/petrol ether 40/60 gavethe intermediate diamide as a colourless powder (1.64g), mp 196°-197°.

(c)N-[2-Hydroxy-2-phenyl]ethyl-N'-[2-[3,4-Di(phenylmethoxy)-2-[2-[3-(phenylmethoxy)phenyl]ethyl]phenyl]hexane-1,6-diamine

A solution of the diamide intermediate from step (b) (1.5g) in drytetrahydrofuran (30ml) was stirred under an atmosphere of nitrogenduring the addition of a 1M solution of borane in tetrahydrofuran(10ml). The mixture was heated to reflux temperature for 24 hours.

Methanol (50ml) was added to the cooled solution and the mixtureevaporated to dryness. The residue was dissolved in methanol (50ml) andconcentrated hydrochloric acid (5ml) added. The solution was stirred at20° for 5 hours. The solution was evaporated to give a solid whichcrystallised from isopropanol to give 1.25g of the dihyrochloridemonohydrate salt of the sub-title compound, mp 192°-194°.

(d)3-[2-[3-Hydroxyphenyl]ethyl]-4-[2-[6-[2-hydroxy-2-phenylethylamino]1hexylamino]-1,2-benzendiol

A solution of the diamine intermediate from step (c) (1.5g) in methanol(50ml) containing a 10% Palladium on charcoal catalyst (0.15g) washydrogenated at 45 psi of 18 hours. The catalyst was removed byfiltration and the solution evaporated to give an oil. Trituration withhot isopropanol then ether gave a colourless solid (0.81 g). The solidwas purified by semi-preparative reverse phase HPLC (Dynamax-60A column)eluting with water with 0.1% trifluoroacetic acid/methanol (1:1) to giveafter evaporation (0.48 g) of the hydrochloride trifluoroacetatehemihydrate mixed salt of the title compound, mp decomposes 100°.

Example 93-[2-[3-Hydroxyphenyl]ethyl]-4-[2-[7-[2-phenylethylamino]-4-hydroxyheptylamino]ethyl]-1,2-benzenediol

(a) N-[2-Phenylethyl]-2,3,4,5-tetrahydro-5-oxo-2-furanpropanamide

A solution of 2,3,4,5-tetrahydro-5-oxo-2-furanpropanoic acid (7.9 g) andN,N-carbonyldiimidazole (8.1 g) in dry dichloromethane (100 ml) wasstirred under nitrogen at 20° for 30 minutes and a solution of2-phenylethylamine (6.05 g) in dry dichloromethane (20 ml) was thenadded. The mixture was stirred at 20° for 2 hours. The solution waswashed with 2N hydrochloric acid, saturated sodium bicarbonate solution,water, dried (MgSO₄), filtered and evaporated to give an oil whichsolidified on standing. Crystallisation from toluene gave the amide asfluffy crystals (10.4 g), mp 86°-87°.

(b)N-[2-[3,4-Di(phenylmethoxy)-2-[2-[3-(phenylmethoxy]phenyl]ethyl]phenyl]ethyl]-N'-[2-phenylethyl]-4-hydroxyheptane-1,7-diamide

A solution of the intermediate step (a) (1.3 g) and3,4-Di(phenylmethoxy)-2-[2-[3-(phenylmethoxy)phenyl]ethyl]benzeneethanamine(5.3 g) in dry xylene (100 ml) was heated to reflux temperature for 5hours. Evaporation and trituration of the residue with ether gave theimpure amide as a beige solid (2.5 g). The solid was purified by flashchromatography (Merck 9385 Silica gel) eluting with chloroform 20%methanol to give the sub-title compound as a beige solid (2 g), mp132°-133°.

(c)N-[2-[3,4-Di(phenylmethoxy)-2-[2-[3-(phenylmethoxy]phenyl]ethyl]phenyl]ethyl]-N'-[2-phenylethyl]-4-hydroxyheptane-1,7-diamine

A solution the diamide intermediate step (b) (2 g) in drytetrahydrofuran (50 ml) was stirred under an atmosphere of nitrogenduring the addition of a 1M solution of borane in tetrahydrofuran (15ml). The mixture was heated to reflux temperature for 16 hours. Methanol(50 ml) was added to the cooled solution and the mixture evaporated todryness. The residue was dissolved in methanol (20 ml) and concentratedhydrochloric acid added (2 ml). The solution was stirred at roomtemperature for 16 hours. The precipitate was filtered and the solidcrystallised from methanol to give 1.6 g of the dihydrochloride salt ofthe sub-title compound, mp 221°-223°.

(d)3-[2-[3-Hydroxyphenyl]ethyl]-4-[2-[7-[2-phenylethylamino]-4-hydroxyheptylamino]ethyl]-1,2-benzenediol

A solution of the diamine intermediate from step (c) (1.55 g) inmethanol (150 ml) was hydrogenated over a 10% Palladium on charcoalcatalyst (0.15 g) at atmospheric pressure for 24 hours.

The catalyst was removed by filtration and the filtrate evaporated toleave 0.85 g of the dihydrochloride hydrate salt of the title compound,mp 64°-66° decomposes.

We claim:
 1. Compounds of formula I, ##STR12## in which one of R₃₀ andR₄₀ represents a group Ra, ##STR13## and the other of R₃₀ and R₄₀represents hydrogen or halogen, R₆₀ represents a group Rb,

    CH.sub.2 XCH.sub.2 YCHER.sub.15 ZR.sub.10                  Rb

wherein X represents a C2 to C8 alkylene chain optionally interrupted bya double bond or by S(O)_(n), wherein n is 0, 1 or 2, Z represents a C1to C3 alkylene chain, each of X and Z being optionally substituted by OHor one or more alkyl C1 to C6, Y represents NR₇₀, NR₇₀ representshydrogen, alkyl C1 to C6 or (CH₂)_(q) R₁₁, R₁₀ and R₁₁ independentlyrepresent phenyl substituted by one or more substituents R₂₃, which maybe the same or different; or R₁₀ represents a saturated carbocyclicgroup, R₁₅ represents hydrogen, alkyl C1 to C6, or together with R₂₃forms a (CH₂)p chain, wherein p represents 0, 1 or 2, R₂₀, R₂₁, R₂₂ andR₂₃ independently represent hydrogen, alkyl C1 to C6, NHR₂₅, SH, NO₂,halogen, CF₃, SO₂ R₂₆, CH₂₀ H or OH, wherein R₂₅ represents hydrogen,alkyl C1 to C6 or alkanoyl C1 to C6 and R₂₆ represents alkyl C1 to C6 orNH₂, m represents 2, 3 or 4, q represents an integer from 1 to 6inclusive, provided that (a) when R₁₅, R₂₁, R₂₂, R₂₃, R₄₀, and R₇₀represent hydrogen, m represents 2, X represents unsubstituted anduninterrupted (CH₂)₄, Z represents CH₂, R₁₀ represents phenyl, then R₂₀does not represent hydrogen or 4-OH, and (b) when R₄₀ representshydrogen, then in addition Y may represent 0 or NH and R₁₀ may representpyridyl, alkyl C1 to C6 or hydrogen, and pharmaceutically acceptablesalts and solvates thereof.
 2. A compound according to claim 1, whereinR₁₀ represents phenyl substituted by one or more substituents R₂₃, whichmay be the same or different.
 3. A compound according to claim 1,wherein R₂₃ independently represents one or more of hydrogen, halogen,hydroxy, NH₂, NHSO₂ alkyl C 1 to 6, NO₂ or alkyl C 1 to
 6. 4. A compoundaccording to claim 1, wherein R₂₀, R₂₁ and R₂₂ independently representshydrogen, hydroxy, alkyl C 1 to 6, halogen or trifluoromethyl.
 5. Acompound according to claim 1, wherein one of R₂₀, R₂₁ or R₂₂ represents3-OH.
 6. A compound according to claim 1, wherein Y represents NH.
 7. Acompound according to claim 1, wherein R₃₀ represents Ra.
 8. A compoundaccording to claim 1, wherein R₄₀ represents hydrogen.
 9. A compoundaccording to claim 1, wherein at least one of R₂₀, R₂₁ and R₂₂represents hydroxy.
 10. A compound according to claim 1, which is3-[2-[3-Hydroxyphenyl]ethyl]-4-[2-[6-[2-phenylethylamino]hexylamino]ethyl]-1,2-benzenediol,ora pharmaceutically acceptable salt or solvate thereof.
 11. A compoundaccording to claim 1, which is 3-[2-[3-Hydroxyphenyl]ethyl]-4-[2-[4-[2-phenylethylamino]butylamino]ethyl]-1,2-benzenediol3-[2-[3Hydroxyphenylethyl]-4-[2-[8-[2-phenylethylamino]octylamino]ethyl]-1,2-benzenediol4-[2-[6-[2-Cyclohexylethylamino]hexylamino]ethyl]-3-[2-[3-hydroxyphenyl]ethyl]-1,2-benzenediol3-[2-[3-Hydroxyphenyl]ethyl]-4-[2-[6-[2-[4-methylphenyl]ethylamino]hexylamino]ethyl]-1,2-benzenediol3-[2-[3-Hydroxyphenyl]ethyl]-4-[2-[6-[2-[3-hydroxyphenyl]ethylamino]hexylamino]ethyl]-1,2-benzenediol4-[2-[6-[6-Hexylamino]hexylamino]ethyl]-3-[2-[3-hydroxyphenyl]ethyl]-1,2-benzendiol4-[2-[6-[2-[4-Chlorophenyl]ethylamino]hexylamino]ethyl]-3-[2-[3-hydroxyphenyl]ethyl]-1,2-benzediol4-[2-[6-[2,3-Dihydro-1H-indene-2yl amino]hexylamino]ethyl]-3-[2-[3-hydroxyphenyl]ethyl]-1,2-benzenediol3-[2-[3-Hydroxyphenyl]ethyl]-4-[2-[6-[2-[4-pyridyl]ethylamino]hexylamino]ethyl]-1,2-benzenediol3-[2-[3-Hydroxyphenyl]ethyl]-4-[2-[6-[2-phenylethylamino]hexylamino]ethyl]-1,2-benzenediol3-[2-[3-Hydroxyphenyl]ethyl]-4-[2-[6-[2-[4-hydroxyphenyl]ethylamino]hexylamino]ethyl-1,2-benzenediol3-[2-[3-Hydroxyphenyl]ethyl]-4-[2-[3-[2-[2-phenylethylamino]ethylthio]propylamino]ethyl]-1,2-benzenediol3-[2-[3-Hydroxyphenyl]ethyl]-4-[2-[3-[2-[2-phenylethylamino]ethanesulphonyl]propanylamino]ethyl]-1,2-benzenediol3-[2-[3-Hydroxyphenyl]ethyl]-4-[2-[6-[2-[4-nitrophenyl]ethylamino]hexylamino]ethyl]-1,2-benzenediol4-[2-[6-[2-[4-Aminophenyl]ethylamino]hexylamino]ethyl]-3-[2-[3-hydroxyphenyl]ethyl]-1,2-benzenediol4-[2-[6-[2-[3,4-Dihydroxy-2-[2-[3-hydroxyphenyl]ethyl]phenyl]ethylamino]hexylamino]ethyl]-3-fluoro-1,2-benzenediol4-[2-[6-[2-[3-Fluoro-4-hydroxyphenyl]ethylamino]hexylamino]ethyl]-3-[2-[3-hydroxyphenyl]ethyl]-1,2-benzenediol3-[2-[3-Methylphenyl]ethyl]-4-[2-[6-[2-phenylethylamino]hexylamino]ethyl]-1,2-benzenediol4-[2-[6-[2-[4-Hydroxyphenyl]ethylamino]hexylamino]ethyl]-3-[2-[3-methylphenyl]ethyl]-1,2-benzenediol3-[2-[3-Hydroxyphenyl]ethyl]-4-[2-[8-[2-[4-hydroxyphenyl]ethylamino]octylamino]ethyl]-1,2-benzenediol4-[2-[6-[2-Phenylethylamino]hexylamino]ethyl]-3-[2-[3-[trifluoromethyl]phenyl]ethyl]-1,2-benzenediol3-[2-[3,5-Dihydroxyphenyl]ethyl]-4-[2-[6-[2-phenylethylamino]hexylamino]ethyl]-1,2-benzenediol4-[2-[6-[2-[3,4-Dihydroxyphenyl]ethylamino]hexylamino]ethyl]-3-[2-[3-hydroxyphenyl]ethyl]-1,2-benzenediol3-[3-[3-Hydroxyphenyl]propyl]-4-[2-[6-[2-phenylethylamino]hexylamino]ethyl]-1,2-benzenediol3-[3-[3-Hydroxyphenyl]propyl]-4-[2-[6-[2-[4-hydroxyphenyl]ethylamino]hexylamino]ethyl]-1,2-benzenediol4-[2-[6-[2-[2,3-Dihydroxyphenyl]ethylamino]hexylamino]ethyl]-3-[2-[3-hydroxyphenyl]ethyl]-1,2-benzenediol3-[2-[3-Chlorophenyl]ethyl]-4-[2-[6-[2-phenylethylamino]hexylamino]ethyl]-1,2-benzenediol3-[2-[3-Chlorophenyl]ethyl]-4-[2-[6-[2-[4-hydroxyphenyl]ethylamino]hexylamino]ethyl]-1,2-benzenediol4-[2-[6-[2-Cyclohexylethylamino]hexylamino]ethyl]-3-[2-[4-hydroxyphenyl]ethyl]-1,2-benzenediol3-[2-[4-Hydroxyphenyl]ethyl]-4-[2-[6-[2-[4-hydroxyphenyl]ethylamino]hexylamino]ethyl]-1,2-benzenediol3-[4-[3-Hydroxyphenyl]butyl]-4-[2-[6-[2-phenylethylamino]hexylamino]ethyl]-1,2-benzenediolE-3-[2-[3-Hydroxyphenyl]ethyl]-4-[2-[6-[2-phenylethylamino]-3-hexenylamino]ethyl]-1,2-benzenediolN-[4-[2-[6-[2-[3,4-Dihydroxy-2-[2-[2[3-hydroxyphenyl]ethyl]phenyl]ethylamino]hexylamino]ethyl]phenyl]methanesulphonamide4-[2-[6-)2-Phenylethoxy)]hexylamino]ethyl-3-[2-[3-hydroxyphenyl]ethyl]-1,2-benzenediol3-[2-[3-Hydroxyphenyl]ethyl]-4-[2-[7-[2-phenylehtylamino]heptylamino]ethyl]-1,2-benzenediol3-[2-[3-Hydroxyphenyl]ethyl]-4-[2-[9-[2-phenylethylamino]nonylamino]ethyl]-1,2-benzenediol3-[2-[3-Hydroxyphenyl]ethyl]-4-[2-[10-[2-phenylethylamino]decylamino]ethyl]-1,2-benzenediol3-[2-[3-Hydroxyphenyl]ethyl]-4-[2-[5-[2-phenylethylamino]-3-methylpentylamino]ethyl]-1,2-benzenediol3-[2-[3-Hydroxyphenyl]ethyl]-4-[2-[5-[2-phenylethylamino]-3,3-dimethylpentylamino]ethyl]-1,2-benzenediol3-[2-[3-Hydroxyphenyl]ethyl]-4-[2-[5-[2-phenylethylamino]pentylamino]ethyl]-1,2-benzenediol3-[2-[3-Hydroxyphenyl]ethyl]-4-[2-[6-[N-methyl-N-2-phenylethylamino]hexylamino]ethyl]-1,2-benzenediol3-[2-[3-Hydroxyphenyl]ethyl]-4-[2-[6-[2-[N,N'-di-[2-phenylethyl]amino]hexylamino]ethyl]-1,2-benzenediol3-[2-[3-Hydroxyphenyl]ethyl]-4-[2-[6-[N-[2-[4-hydroxyphenyl]ethyl]-N-[2-phenylethyl]amino]hexylamino]ethyl]-1,2-benzenediol6-Chloro-3-[2-[3-Hydroxyphenyl]ethyl]-4-[2-[6-[2-phenylethylamino]hexylamino]ethyl]1,2-benzenediol6-Chloro-3-[2-[4-Hydroxyphenyl]ethyl]-4-[2-[6-[2-phenylethylamino]hexylamino]ethyl]1,2-benzenediol3-[2-[3-Hydroxyphenyl]ethyl]-5-[2-[6-[2-phenylethylamino]hexylamino]ethyl]1,2-benzenediol5-[2-[3-Hydroxyphenyl]ethyl]-4-[2-[6-[2-phenylethylamino]hexylamino]ethyl]1,2-benzenediol3-[2-[3-Hydroxyphenyl]ethyl]-4-[2-[6-[2-hydroxy-2-phenylethylamino]hexylamino]ethyl]-1,2-benzenediol3-[2-[3-Hydroxyphenyl]ethyl]-4-[2-[7-[2-phenylethylamino]-4-hydroxyheptylamino]ethyl]-1,2-benzenediolora pharmaceutically acceptable salt or solvate thereof.
 12. Apharmaceutical composition comprising a compound according to any one ofthe preceding claims in admixture with a pharmaceutically acceptableadjuvant, diluent or carrier.
 13. A method of treatment of renal failurewhich comprises administration of an effective amount of a compoundaccording to claim 1 to a patient suffering from such a condition.